ES2870718T3 - Colchicine sustained-release formulation and methods for establishing the same - Google Patents

Abstract

A sustained release formulation of colchicine as an active ingredient, which formulation comprises: (a) granules comprising between 0.1 and 0.6 mg of colchicine or a pharmaceutically acceptable salt thereof; (b) a binder, wherein the binder is 6 mPa-s hydroxypropylmethylcellulose (HPMC) in an amount of 1% to 30% (p.h.) of the formulation; (c) a retarding agent in an amount of 5% to 40% (p.h.) of the formulation, wherein the retarding agent is a spray agglomerated mixture of equal parts by weight of HPMC with a viscosity grade of 4000 mPa- s and lactose monohydrate (Retalac®); and (d) at least one pharmaceutically acceptable carrier admixed with the granules, wherein the sustained release formulation is a tablet.

Description

DESCRIPTION

Colchicine sustained-release formulation and methods for establishing the same

Background of the invention

Colchicine, whose chemical name is (-) - N - [(7S, 12aS) -1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo [a] heptalene-7- il] - acetamide, is an alkaloid found in extracts of Colchicum autumnale, Gloriosa superba and other plants. It is a microtubule disrupting agent that is used in the treatment of diseases that can be treated, alleviated or prevented with an anti-inflammatory treatment.

Colchicine is widely recognized as a valid treatment for acute flare-ups of gouty arthritis, familial Mediterranean fever (FMF), and Behpet's disease. It has also been used to treat various inflammatory disorders prone to fibrosis. In recent years, colchicine has been proposed to be effective in the treatment of cardiovascular diseases.

Specifically, colchicine has been proposed as one of the first treatment options for recurrent pericarditis (class I indication) and as an option for acute pericarditis (class lia indication) in the 2004 European guidelines on the management of pericardial diseases (Maisch et al., 2004, Guidelines on the Diagnosis and Management of Pericardial Diseases, Eur Heart J., 25, 916-928).

Imazio et al. (2005, Circulation, 112 [13], 2012-2016) demonstrated that colchicine was effective for the treatment and prevention of recurrent pericarditis in a prospective, randomized, open-label study of 120 patients with a first episode of acute pericarditis (idiopathic, viral, postpericardiotomy syndromes and connective tissue diseases), which were randomly assigned to conventional treatment with aspirin or conventional treatment plus colchicine (1.0 to 2.0 mg on the first day and thereafter). 0.5 to 1.0 mg / day for 3 months). The primary endpoint was the recurrence rate, which was significantly reduced from 32.3% to 10.7% at 18 months in the colchicine group (p = 0.004).

Also, the same group showed that colchicine could be effective after failure of conventional treatment to control acute pericarditis (Imazio et al., 2005, Arch InternMed, 165 [17], 1987-91). In a prospective, randomized, and open-label design, 84 consecutive patients with a first episode of recurrent pericarditis were randomly assigned to either conventional treatment with aspirin alone or conventional treatment plus colchicine (1.0-2.0 mg on the first day and , then 0.5-1.0 mg / day for 6 months). The primary endpoint was the recurrence rate, which was significantly reduced in the colchicine group (actuarial rates at 18 months were 24.0% versus 50.6% with conventional treatment).

Colchicine has also been shown to be effective for secondary prevention of recurrent pericarditis (Imazio et al., 2011, Ann. Intern. Med., 155 [7], 409-14). Colchicine has also been proposed to reduce postpericardiotomy reactions that appear as pericarditis (Imazio et al., 2011, Am. Heart J., 162 [3], 527 532; Meurin and Tabet [2011], Arch. Cardiovasc. Dis., 104 [8-9], 425-427).

Colchicine for the treatment of post-pericardiotomy syndrome (PPS) was first tested in a preliminary, prospective, open-label, randomized trial of colchicine (1.5 mg / day) compared with placebo from the third postoperative day in 163 patients. who underwent cardiac surgery (Finkelstein et al., 2002, Herz, 27, 791-194).

The efficacy of colchicine for the prevention of PPS has also been demonstrated in a randomized, multicenter, double-blind trial, in which 360 patients (with a mean age of 65.7 + 12.3 years, 66% men), 180 in each treatment group were randomized to receive placebo or colchicine (1.0 mg twice daily for the first day, followed by a maintenance dose of 0.5 mg twice daily for 1 month in patients> 70 kg, and doses reduced by half for patients weighing 70 kg or intolerant to the highest dose) on the third postoperative day (Imazio et al., 2010, European Heart Journal, 31, 2749-2754).

In another study, the efficacy of colchicine for cardiovascular disease was demonstrated. In this prospective, randomized, blind observer end-point clinical trial, 532 patients with stable coronary disease receiving aspirin or clopidogrel (93%) and statins (95%) were randomly assigned 0.5 mg / day of colchicine or no colchicine with a follow-up for a mean of 3 years (Nidorf et al., 2013, JACC, 61 (4), 404-410). This study demonstrated that colchicine given at 0.5 mg / day in addition to statins and other standard secondary prevention treatments appeared to be effective in preventing cardiovascular events in patients with stable coronary disease.

For the treatment of gout, the recommended dose of colchicine (COLCRYS®) is 1.8 mg / day in one or more doses over a period of one hour. For adults with gout, treatment begins with a dose of 1.2 mg at the first symptoms, followed by 0.6 mg one hour later. (Physician's Desk Reference, 68th ed., 2014).

COLCRYS® is an immediate release formulation. Adverse effects associated with the administration of COLCRYS® include, but are not limited to, nausea, vomiting, abdominal pain, diarrhea, hair loss, weakness, nerve irritation, severe anemia, low white blood cell counts and low platelet level. (Physician's Desk Reference, 68th ed., 2014).

CN 101732274 A describes a colchicine bilayer sustained release tablet with a rapid release layer and a sustained release layer. The quick release layer consists primarily of colchicine, a disintegrant, a diluent, a lubricant, and an adhesive. The sustained release layer is primarily composed of colchicine, a sustained release matrix, a retarding agent, a diluent, and an adhesive. The weight ratio of colchicine in the rapid-release layer to colchicine in the sustained-release layer is (0.25-0.42): 1, and the weight ratio of the rapid-release layer to relative to the sustained release layer it is 1: 2 to 1: 4.

CN 101485638 A describes a colchicine double layer osmotic pump controlled release tablet and a method for preparing the same. The controlled-release tablet has a dual-layered core consisting of a drug-containing layer and a push layer. The tablet also comprises a layer of a coating membrane that is coated on the outer surface of the core of the double-layer tablet and belongs to a semi-permeable coating membrane. The covering membrane consists of a drug release hole on the surface of the drug-containing layer. In the core of the tablet, the layer containing the drug contains the colchicine, whose weight percentage with respect to the weight percentage of the core of the double-layer tablet is between 0.1 and 1.0 percent and a suspending agent, active ingredients of osmotic pressure and pharmaceutical adjuvants. The push layer contains a blowing agent, a permeation enhancer, a retarder and a binder, a wetting agent, a lubricant, and a thickening agent. The weight of the coating membrane relative to the weight of the tablet core is between 10 and 20 percent, and the opening of the drug release port on the surface of the drug-containing layer of the coating membrane ranges between 0.2 and 2 millimeters.

CN 101485637 A describes a structural controlled release colchicine tablet or capsule, comprising colchicines and structural materials with a controlled release function. The structural materials contain hydrophilic polymers whose weight relative to the weight of the tablet is at least 20 percent and other pharmaceutical adjuvants. The tablet or capsule comprises the following components by weight percent: 0.01 to 1.0 percent colchicine, 20 to 85 percent hydrophilic polymer, 1 to 30 percent retarder, 20 to 60 percent thickening agent and 0.1 to 2 percent lubricant.

The present invention addresses these and other needs by providing a modified colchicine formulation characterized by sustained release of an active ingredient. This invention further provides an effective dosage form of a daily dose of colchicine or its salts, which can improve patient cooperation and also reduce some of the side effects of colchicine compared to current or higher daily doses of colchicine formulations. immediate-release colchicine.

BRIEF SUMMARY OF THE INVENTION

According to a first aspect of the invention illustrated herein, a sustained release formulation of colchicine as active ingredient is provided, the formulation of which comprises (a) granules comprising between 0.1 and 0.6 mg of colchicine or a pharmaceutically acceptable salt Of the same; (b) a binder, in which the binder is hydroxypropylmethylcellulose (HPMC) of 6 mP's in an amount of 1% to 30% (p.h.) of the formulation; (c) a retarding agent in an amount of 5% to 40% (ph) of the formulation, wherein the retarding agent is a spray-bonded mixture of equal parts by weight of HPMC with a viscosity grade of 4000 mPa ^ s and lactose monohydrate (Retalac®); and (d) at least one pharmaceutically acceptable excipient in admixture with the granules, when the sustained release formulation is a tablet.

The present disclosure describes a method of treating or preventing cardiovascular disease in a subject, which is intended to administer to the subject a therapeutically effective amount of a sustained release colchicine formulation.

The present disclosure also describes a method of treating or preventing an inflammatory disease in a subject, which is intended to administer to the subject a therapeutically effective amount of a sustained release colchicine formulation.

According to a second aspect of the invention illustrated herein, there is provided a process for preparing a colchicine sustained release tablet consisting of the following steps: (A) forming a solution by dissolving colchicine in water, in which the colchicine is provided in such an amount that the resulting tablet will comprise 0.25-0.75% (ph) of colchicine; (B) Add a diluent and a binder to the solution from step A and form a wet granulation, in which the binder is hydroxypropylmethylcellulose (HPMC) of 6 mPa ^ s and is added in such an amount that the resulting tablet comprises 1% to the 30% (ph) binder; (C) dry the wet granulation from step B; (D) Mixing the dry granulation from step C with a retarding agent, a diluent, a slipper, and a lubricant, wherein the retarding agent is a spray-bonded mixture of equal parts by weight of HPMC with a viscosity grade of 4000 mPa ^ s and lactose monohydrate (Retalac®) and is added in such an amount that the resulting tablet comprises between 5% and 40% (ph) of retarding agent; and (E) compressing the final granulation from step D into a tablet.

This disclosure also describes a compressed and molded sustained release therapeutic composition comprising colchicine and excipients combined in a matrix, characterized by a prolonged, slow and relatively regular progressive release of colchicine after administration, wherein the excipients include hypromellose, and the total amount of excipients is effective to bind the colchicine in a sustained release solid matrix and is not less than 99 percent of the weight of said compressed molded composition.

This disclosure also describes a molded compressed colchicine sustained release tablet that is prepared by wet granulating a sufficient amount of colchicine to comprise about 0.25 to about 0.75 percent of the total composition with the excipients, taking into account that the excipients comprise the following: lactose monohydrate from about 10 to about 80 percent of the total composition, pregelatinized starch from about 5 to about 50 percent of the total composition, hypromellose 6 mPa * s from about 1 to about 30 percent percent of the total composition, purified water (qs), Retalac from about 5 to about 40 percent of the total composition, talc from about 0.5 to about 5 percent of the total composition, and stearic acid from about 0.5 to approximately 5 percent of the total composition.

BRIEF DESCRIPTION OF THE GRAPHS / FIGURES

Figure 1 shows dissolution profiles for sustained release colchicine formulations containing 10%, 15%, and 20%, respectively, of an exemplary retarding agent.

Figure 2 shows dissolution profiles for sustained release colchicine formulations containing 30% of an exemplary retarding agent and tablet hardnesses of 50 N and 130 N, respectively.

Figure 3 shows the dissolution profiles for sustained release colchicine formulations according to Figures 1 and 2.

Figure 4 shows dissolution profiles for a sustained release colchicine formulation containing 0% of an exemplary retarding agent.

DETAILED DESCRIPTION OF THE INVENTION

1. Definitions

For the purposes of this invention, the term "colchicine" includes colchicine or any of its pharmaceutically acceptable salts.

"Pharmaceutically acceptable" indicates that it is generally safe, non-toxic and not undesirable for biological or other reasons, and includes what is acceptable for veterinary use as well as for human pharmaceutical use.

"Pharmaceutically acceptable salts" includes derivatives of colchicine, in which colchicine is modified by making acid or base addition salts thereof, and also refers to pharmaceutically acceptable solvates, including hydrates and cocrystals of such compounds and salts. . Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid addition salts of basic residues such as amines, alkaline or organic addition salts of acid residues and the like, and combinations comprising one or more of the aforementioned salts. . Pharmaceutically acceptable salts include non-toxic salts and quaternary ammonium salts of colchicine. For example, non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; Other acceptable inorganic salts include metal salts such as the sodium salt, potassium salt, cesium salt, and the like; and alkaline earth metal salts such as calcium salt, magnesium salt and the like, and combinations comprising one or more of the aforementioned salts. Pharmaceutically acceptable organic salts include salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymax, phenylacetic, glutamic, benzoic, salicylic, mesyl , esyl, besyl, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC— (CH2) n-COOH, where n is 0-4 and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt and the like; and amino acid salts such as arginate, asparaginate, glutamate, and the like; and combinations comprising one or more of the aforementioned salts; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt and the like; and amino acid salts such as arginate, asparaginate, glutamate, and the like; and combinations comprising one or more of the aforementioned salts. This document covers all forms of colchicine derivatives, including all forms crystalline, amorphous and polymorphic. Specific colchicine salts include colchicine hydrochloride, colchicine dihydrochloride, and cocrystals, hydrates, or solvates thereof.

The 'pharmacokinetic parameters' describe the in vivo characteristics of an active agent (or a metabolite or an indirect marker of the active agent) over time, such as plasma concentration (C), Cmax, Cn, C24, Tmax and AUC. "Cmax" is the measured plasma concentration of the active agent at the point of maximum or peak concentration. "Cmin" is the measured plasma concentration of the active agent at the lowest concentration point. "Cn" is the measured plasma concentration of the active agent at approximately n hours after its administration. "C24" is the measured plasma concentration of the active agent approximately 24 hours after its administration. The term "Tmax" refers to the time when the measured plasma concentration of the active agent is highest after administration of the active agent. "AUC" is the area under the curve of a graph of the measured plasma concentration of an active agent versus time, measured from one point in time to another. For example, AUC0-t is the area under the plasma concentration vs. time point curve from time 0 to time t, where t may be the last measurable plasma concentration time point for an individual formulation. The AUC0- ~ or AUC0-INF is the calculated area under the plasma concentration curve with respect to time, from time 0 to infinity. In steady-state studies, AUC0-T is the area under the plasma concentration curve during the dosing interval (i.e., from time 0 to time t (tau), where tau is the duration of the dosing interval. Other pharmacokinetic parameters are the Ke or Kel parameter, the terminal elimination constant calculated from a semilogarithmic plot of the plasma concentration curve versus the time curve; tl / 2, the terminal elimination half-life, calculated as 0.693 / Kel; CL / F indicates the apparent total body clearance after administration, calculated as Total Dose / AUC ~ total; and Varea / F indicates the apparent total volume of distribution after administration, calculated as Total Dose / (AUC ~ total x Kel).

"Efficacy" refers to the ability of an active agent administered to a patient to produce a therapeutic effect in that patient.

"Bioavailability" refers to the degree or rate at which an active agent is absorbed into a living system or is available at the point of physiological activity. For active agents that are intended to be absorbed into the bloodstream, bioavailability data for a given formulation can provide an estimate of the relative fraction of the administered dose that is absorbed into the systemic circulation. "Bioavailability" can be characterized by one or more pharmacokinetic parameters.

A "dosage form" refers to a unit of administration of an active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, creams, ointments, suppositories, inhalable forms, transdermal forms, and the like.

An "immediate release formulation" refers to a formulation that releases greater than or equivalent to about 80% of the pharmaceutical agent in less than or equivalent to about 30 min.

For the purposes of this application, an enhancing agent ("enhancer") is defined as any non-pharmaceutical active ingredient that enhances the therapeutic potential of a formulation.

"Sustained release" is defined herein as the release of a pharmaceutical agent continuously over an extended period of time.

By "extended period of time" is meant a continuous period of time greater than approximately 1 hour, greater than approximately 4 hours, greater than approximately 8 hours, greater than approximately 12 hours, greater than approximately 16 hours, or up to more than approximately 24 hours. .

As used herein, unless otherwise indicated, the 'release rate' or 'dissolution rate' of a medicine refers to the amount of medicine released by a dosage form by unit of time, for example, milligrams of medicine released per hour (mg / h) or a percentage of the total dose of medicine released per hour. Typically, drug release rates for dosage forms are measured as an in vitro drug release rate, that is, an amount of drug released from the dosage form per unit of time measured under the appropriate conditions and in a suitable liquid. . The release rates referred to herein are determined by placing a dosage form to be tested in medium in an appropriate dissolution bath. Aliquots of the medium, collected at preset intervals, are then injected into a chromatographic system equipped with an appropriate detector to quantify the amounts of drug released during the study intervals.

Side effect is defined as a side and generally adverse effect of a drug.

Terms such as "in treatment", "treatment", "treat", "alleviate" or "mitigate" refer to both 1) the measures therapeutics that cure slow, lessen symptoms, reverse, or halt the progression of a diagnosed disease or disorder; as a 2) prophylactic or preventive measures that prevent or slow the development of a specific disease or condition. So the patients in need of treatment are those who already have the disorder, those who are prone to the disorder, and in whom the disorder must be prevented. Beneficial or desired clinical outcomes include, but are not limited to, relief of symptoms, lessening of disease magnitude, stabilization (i.e., not worsening) of disease, delay or slowing of disease progression, improvement or palliation of disease. disease status, and remission (either partial or total), either detectable or undetectable. "Treatment" can also refer to a prolongation of survival compared to expected survival if treatment is not received. Patients in need of treatment are those who already have the disease or disorder, those who are prone to the disease or disorder, and in whom the disease or disorder must be prevented.

The terms "subject", "individual", "animal", "patient" or "mammal" refer to any subject, specifically, a mammalian subject, for whom a diagnosis, prognosis or treatment is desired. Mammalian subjects include humans, domestic animals, farm animals, and zoo, sports or companion animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows, bears, etc. The meaning of the terms "eukaryote," "animal," "mammal," and so on. it is well known in the art and can, for example, be deduced from Wehner und Gehring (1995; Thieme Verlag). In the context of this invention it is also envisaged that animals that are important from an economic, agronomic or scientific point of view are to be treated. Scientifically important organisms include, but are not limited to, mice, rats, and rabbits. Some examples, without limitation, of animals of agronomic importance are sheep, cattle and pigs, while, for example, cats and dogs can be considered animals of economic importance. In one of its presentations, the subject or patient is a mammal; in another, the subject or patient is a human or non-human mammal (e.g., guinea pig, hamster, rat, mouse, rabbit, dog, cat, horse, monkey, ape, a marmoset, a papio, a gorilla, a chimpanzee, an orangutan, a gibbon, a sheep, cattle or a pig); it is preferable that the subject or patient is a human being.

II. Colchicine

Next, the colchicine used according to the present invention will be described in detail. The chemical structure of colchicine (ChemID 2012) is as follows:

The chemical name of colchicine is as follows: N [5,6,7,9-tetrahydro-l, 2,3,10-tetramethoxy 9-oxobenzo [a] heptalene-7-yl], (S) -acetamide; molecular formula: C 22H25NO6; CAS number: 64-86-8.

Colchicine is an anti-inflammatory drug with a long history in human medicine, used for the symptomatic treatment of inflammatory diseases, mainly gout. It is a natural product that can be extracted from two plants of the liliaceae family, Colchicum autumnale and Gloriosa superba. Colchicine is a tricyclic alkaloid and has a molecular mass of 399,437. The active substance colchicine, as well as its tablet formulation, is listed in several national and international pharmacopoeias, such as the United States Pharmacopeia (USP).

The positive effect of its plant source in the treatment of rheumatism and inflammation was first described around 1500 BC. C. in Egypt. Its use in gout was first described about 1500 years ago (Graham and Roberts, 1953, Ann Rheum Dis 12 (1): 16-9). Today, the therapeutic value of colchicine is well established in a number of inflammatory diseases and is approved by the FDA for the prophylaxis and treatment of outbreaks of acute gout and familial Mediterranean fever (FMF). Other important, established but unapproved uses include, among others, Behget's disease and recurrent pericarditis. In all known indications, it is generally administered orally as solid tablets in concentrations of 0.5 to 0.6 mg / tablet (for example, in Europe and the United States, respectively). The pharmacotherapeutic mechanism of action of colchicine in various disorders is not fully understood, although the drug is known to preferentially accumulate in leukocytes, specifically neutrophils, which is important for its therapeutic effect. Three main interactions of colchicine with specific proteins modulate its pharmacokinetics: tubulin, cytochrome P4503A4 (CYP3A4), and P-glycoprotein. Most of the therapeutic effects of the drug are assumed to be related to its ability to bind p-tubulin, thus inhibiting microtubule self-assembly and polymerization. The availability of tubulin is essential for various cellular functions such as mitosis. Therefore, colchicine works effectively as a "mitotic poison" or an antimitotic. By inhibiting microtubule self-assembly, colchicine interferes with many cellular functions involved in the immune response, such as modulation of chemokine and prostanoid production, and inhibition of neutrophil and endothelial cell adhesion molecules. Ultimately, it decreases neutrophil degranulation, chemotaxis, and phagocytosis, thus reducing the initiation and amplification of inflammation. Colchicine also inhibits uric acid crystal deposition (an important process for gout genesis), which is enhanced by low tissue pH, probably by inhibiting glucose oxidation and subsequent lactic acid reduction in leukocytes (Imazio, Brucato et al. 2009, Eur Heart J, 30 (5): 532-9; Cocco, Chu et al. 2010, Eur J Intern Med, 21 (6): 503-8; Stanton, Gernert et al. 2011, Med Res Rev, 31 (3): 443-81). In the treatment of pericarditis, colchicine extracts its therapeutic effect by suppressing acute inflammation of the pericardium. However, the exact cellular and molecular mechanisms of how colchicine relieves pain and inflammation in acute pericarditis and prevents it from recurring are not fully understood.

In the context of the present invention, colchicine can be used for the prevention or treatment of cardiovascular or inflammatory diseases.

III. Sustained release formulations

The present invention further provides a sustained release colchicine formulation for the treatment or prevention of cardiovascular disease or inflammatory disorder in a subject, wherein colchicine is released from the formulation at a constant rate along with a release profile. default or desired. Said release is achieved by incorporating into the formulation a sustained release component and an optional immediate release component. The colchicine formulation of the present invention can be formulated in a dosage form selected from a tablet, lozenge, capsule, tablet, sachet, cachet, blister, granules, or any other form suitable for oral administration.

According to the present invention, the colchicine described herein (ie, inter alia, in the form of a [pharmaceutical] composition) is administered in the form of a sustained-release preparation. Other expressions such as "prolonged release", "controlled release", "modified release" or "preparation" or "delayed release formulation" are understood herein to have the same meaning as "sustained release preparation". Said preparations can, in principle, be presented in any form conceivable to the person skilled in the art and include pharmaceutical forms for oral administration (solid, semisolid, liquid), dermal (dermal patch), sublingual, parenteral (injection), ophthalmic (drops). ophthalmic, gel or ointment) or rectal (suppository), provided that a sustained release is guaranteed.

According to this invention, sustained release preparations encompass all pharmaceutical forms that create a constant release profile of the drug, which makes the drug substance available for a prolonged period of time after its application to the patient. Said extended period of time can be between 10, 20, 30, 40, 50 or 60 minutes and approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours. Prolonged release can also be functionally defined as the release of more than 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99 percent (%) of the colchicine after approximately 10, 20, 30, 40, 50 or 60 minutes and approximately 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours. Sustained release, as used herein, can also be defined as making the colchicine available to the patient regardless of absorption, since the patient may never absorb some of the colchicine. One skilled in the art can easily design various sustained release dosage forms, as described herein, to achieve administration and sustained release of colchicine to the liver or the small and large intestine, to the small intestine only, or to the intestine only. large intestine.

In some of their presentations, sustained-release preparations can be pH independent, allowing these preparations to dissolve in almost any environment. In other presentations, sustained-release preparations can be pH dependent, allowing release to be achieved at some generally predictable location in the lower gastrointestinal tract more distal than it would have been if there had been no delayed-release disturbances. One method of delaying release is, for example, a coating. Any coating should be applied thick enough so that not all of the coating dissolves in gastrointestinal fluids at a pH below about 5, but does dissolve at a pH of about 5 and above. It is envisioned that any anionic polymer exhibiting a pH dependent solubility profile can be used as an enteric coating in the practice of the present invention to achieve delivery to the lower gastrointestinal tract. Polymers and compatible mixtures thereof can be used to provide the coating for the delayed or prolonged release of active ingredients, and some of their properties include, but are not limited to, shellac, also known as purified shellac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in media with a pH > 7.

In some of their presentations, sustained-release preparations can be influenced by the presence of alcohol in the body. The presence of alcohol in a patient's body can increase dissolution of the composition and cause immediate release of the full dose. This effect is known as "rapid dose discharge" and depends on the alcohol solubility of the materials. For sustained-release preparations containing a higher dose for a slow release over 24 hours, for example, this effect can present safety concerns and can even be life-threatening.

To achieve a uniform or continuous release rate, sustained release preparations can be made using sustained release hydrophilic matrices. These extended release hydrophilic matrices are known in the field of drug formulations. For example, one of these hydrophilic matrices is hydroxypropylmethylcellulose (HPMC) or hypromellose. Hydrophilic matrices provide an initial release of the drug in the initial phase, caused mainly by a rapid swelling of the matrix tablet surface, combined with an erosion process that results in an immediate release of the drug distributed near the tablet surface. In one of its presentations, approximately 50%, approximately 45%, approximately 40%, approximately 35%, approximately 30%, approximately 25%, approximately 20%, approximately 15% or approximately 10% of the drug can be released immediately depending on the desired release profile. In one of its presentations, at least about 20% of the drug can be released immediately. In other forms, at least about 20% of the drug can be released in about the first 30 minutes. As used herein, the terms "around" or "approximately" refer to a 10% variation from the indicated values (eg 50%, 45%, 40%, etc.), or in the case of a range of values, it means a variation of 10% of the upper and lower limits of said ranges. For example, "approximately 50%" refers to a range between 45% and 55%. Within the initial swelling of the tablet surface, a gel of the hydrophilic matrix begins to form. This gelling prevents the core of the tablet from dissolving and disintegrating immediately, allowing the main part of the drugs to dissolve slowly over time within this gel structure and diffuse into a solution according to the rules of the law. by Fick. In this formulation approach, the diffusion itself can be triggered by the concentration of the hypromellose and the viscosity of the gel formed, defined on the molecular weight of the hypromellose. Therefore, drug release profiles can be modified by varying the different viscosity grades of hypromellose or its mixtures. All corresponding formulation and process parameters that achieve the intended release profile are common knowledge and can be adjusted by effective development technologies, eg formulation selection and statistical assay designs.

In one of its presentations, the substance responsible for the sustained release of the controlled release formulation can also be mixed with a binder. The binder is added to increase the strength of the granules and tablets during formation. Binders can be added to the formulation in different ways: (1) as a dry powder, which is mixed with other ingredients before wet agglomeration, (2) as a solution, which is used as a agglomeration liquid during agglomeration wet, and is known as a binder in solution, and (3) as a dry powder, which is mixed with the rest of the ingredients before compaction. In this form, the binder is called a dry binder. Solution binders are a common way to incorporate a granular binder. In some presentations, the binder used in the formulation is in the form of a dry powder binder. Some non-limiting examples of useful core binders include hydrogenated vegetable oil, castor oil, paraffin, higher aliphatic alcohols, higher aliphatic acids, long chain fatty acids, fatty acid esters, wax-like materials such as alcohols. fatty acids, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol, hydrophobic and hydrophilic polymers with hydrocarbon main chains and their mixtures. Specific examples of water-soluble polymeric binders include modified starch, gelatin, polyvinylpyrrolidone, cellulose derivatives (eg, hydroxypropylmethylcellulose [HPMC] and hydroxypropylcellulose [HPC]), polyvinyl alcohol, and mixtures thereof. In one of its presentations, the binder is HPMC. In another presentation, the binder is the 6 mPa * s hypromellose. In one of its presentations, the binder may be present in an amount ranging from about 1% to about 30% of the weight of the formulation.

In another embodiment of the invention, the sustained release formulation may include a disintegrant. A disintegrant is an agent used in the pharmaceutical preparation of tablets, which causes them to disintegrate and release their medicinal substances on contact with moisture. In one of its presentations, the disintegrant can be soluble in water to favor the disintegration of a tablet in the stomach. Some non-limiting examples of disintegrants for use in the formulation include sucrose, lactose, specifically lactose monohydrate, trehalose, maltose, mannitol and sorbitol, croscarmellose sodium, crospovidone, alginic acid, sodium alginate, DVB methacrylic acid, cross-linked PVP , microcrystalline cellulose, potassium polacrilin, sodium starch glycolate, starch, pregelatinized starch and their mixtures. In at least one presentation, the disintegrant is selected from microcrystalline cellulose (eg, Avicel PH101), cross-linked polyvinylpyrrolidone (eg, KOLLIDON® CL), cross-linked sodium carboxymethylcellulose (eg, AC-DI-SOL [TM]), starch or starch derivatives such as sodium starch glycolate (for example, EXPLOTAB®), or combinations with starch (for example, PRIMOJEL [TM]), swellable ion exchange resins, such as AMBERLITE (TM) IRP 88, casein formaldehyde (for example, ESMA SPRENG [TM]) and their mixtures.

In another embodiment of the invention, the sustained release formulation may include a diluent or filler. A diluent refers to an inert substance used as a filler to create the desired size, flow properties, and compression characteristics in the preparation of tablets. Some non-limiting examples of diluents for use in the formulation include sucrose, lactose, specifically lactose monohydrate, trehalose, maltose, mannitol and sorbitol, croscarmellose sodium, crospovidone, alginic acid, sodium alginate, DVB methacrylic acid, cross-linked PVP , microcrystalline cellulose, potassium polacrilin, sodium starch glycolate, starch, pregelatinized starch and their mixtures. In one of its presentations, lactose monohydrate is included as a diluent in an amount of from about 10% to about 80%, preferably about 59%, of the weight of the tablet. In one of its presentations, pregelatinized starch is included as a diluent in an amount of about 5% to about 50%, preferably about 7.5%, of the weight of the tablet.

In another of its presentations, the sustained release formulation of the present invention may include a release retarding agent to maintain a uniform release rate of the drug. Examples of retarding agents include, but are not limited to, cellulose ethers, cellulose esters, acrylic acid copolymers, waxes, gums, glyceryl fatty acid esters, and sucrose fatty acid esters. In one of its presentations, the retarding agent is RETALAC® (Meggle), a spray-bonded mixture of 50 parts of lactose monohydrate and 50 parts of hypromellose. The viscosity of the hypromellose used in this case can range from 6 mPa * s to 100,000 mPa * s. In one of its presentations, the viscosity of the hypromellose used is 4000 mPa * s. Adjusting the amount of retarding agent in the composition can alter the release rate of the drug. In one of its presentations, the retarding agent of the formulation of the present invention releases colchicine continuously and uniformly and is adjusted in such a way that approximately 80% of the active principle is released in vitro in the predetermined period of time. By way of example, and without limiting the scope of the invention in any way, the period of time may not be longer than 24 hours, not longer than 16 hours, not longer than 12 hours, not longer than 8 hours, not longer than 6 hours, not more than 4 hours, not more than 3.5 hours or not more than 1.5 hours depending on the desired attributes of the final product. It is understood that the release rate can vary depending on whether the experiment is performed in vitro or in vivo. Therefore, if the desired release rate is between about 1.5 and about 3.5 hours in vitro or between about 1.5 and about 6 hours in vitro, the release rate under in vivo conditions, depending on the conditions experimental, may differ. In one of its presentations, the sustained-release formulation of the formulation of the present invention releases colchicine in a continuous and uniform manner so that approximately 80% of the active principle is released in vitro in a period of time comprised between approximately 1.5 hours and approximately 3.5 hours.

In another embodiment, the sustained release formulation of the present invention may include a glidant. A glider can be used to improve the flow properties of the powder before and during tableting and to reduce caking. Suitable glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, talc, tribasic calcium phosphate, and the like. In one of its presentations, talc is included as a glidant in an amount of about 0.05% to about 5%, preferably about 1%, of the weight of the tablet.

In another embodiment, the sustained release formulation of the present invention may include a lubricant. Lubricants can be added to pharmaceutical formulations to decrease any friction that occurs between the solid and the matrix wall during tablet manufacture. High friction during tabletting can cause a number of problems, including poor quality of tablets (plugging or even fragmentation of tablets during ejection and vertical scratches at the edges of tablets) and can even stop production. . Accordingly, lubricants are added to certain tablet formulations of the present invention that include certain presentations of the formulation described herein. Some, but not limited to, examples of useful core lubricants include glyceryl behenate, stearic acid, hydrogenated vegetable oils (such as hydrogenated cottonseed oil [STEROTEX®]), hydrogenated soybean oil (STEROTEX® HM), and soybean oil. hydrogenated soybean and castor wax (STEROTEX® K), stearyl alcohol, leucine, polyethylene glycol (MW 1450, possibly 4000 and higher), magnesium stearate, glyceryl monostearate, polyethylene glycol, ethylene oxide polymers (for example, available under the trademark CARBOWAX® from Union Carbide, Inc., Danbury, Conn.), sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, colloidal silica, mixtures thereof, and others known in the art. In one of its presentations, stearic acid is included as a lubricant in an amount of about 0.05% to about 5%, preferably about 1%, of the weight of the tablet.

Sweeteners that can also be used in the taste-masking coating of certain presentations of the matrix dosage forms include glucose (corn syrup), dextrose, invert sugar, fructose, and mixtures thereof (when not used as a carrier); saccharin and its various salts, such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Steva Rebaudiana (stevioside); derivatives of chlorine or sucrose such as sucralose; and sugar alcohols such as sorbitol, mannitol, xylitol, and the like. Hydrogenated starch hydrolysates and synthetic sweeteners such as 3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-1-2,2-dioxide, specifically salt potassium (acesulfame-K), and its sodium salts and calcium. Sweeteners can be used alone or in any combination thereof.

The controlled release formulation of the present invention may further contain one or more pharmaceutically acceptable excipients such as adjuvants or granulating agents, colorants, flavors, pH regulators, anti-adhesion agents, glidants and similar excipients normally used in pharmaceutical compositions. In one of its presentations, it may be useful to add a coloring excipient to produce a visual change that avoids its abuse. You can simultaneously change the color of the liquid or the particles, or one independently of the other. Among the suitable coloring excipients, the following may be mentioned: indigo carmine, cochineal carminic acid, orange yellow S, allura red AC, iron oxides, curcumin, riboflavin, tartrazine, quinoline yellow, azorubin, amaranth, carmines, erytosine, 2G red, patented blue V, brilliant blue FCF, chlorophylls, copper complexes of chlorophylls, green S, caramel, brilliant black BN, carbo medicinalis vegetabilis, brown FK and HT, carotenoids, annatto extracts, paprika extracts, lycopene, lutein , canthaxanthin, beet red, anthocyanins, calcium carbonate, titanium dioxide, aluminum, silver, gold or lithol-rubin BK or any other coloring excipient suitable for oral administration.

In one of its presentations, a sustained release formulation can be coated. Coatings can provide a wide variety of functions. In some presentations, the coatings can be used, for example, to achieve delayed release, acid resistance, targeted release in the lower gastro-intestinal tract, and to avoid a bad taste in the mouth. In some presentations, coatings can be used to protect the API / tablet from light and provide better mechanical strength. Of course, it should be appreciated that a coating can also fulfill other functions and one of ordinary skill in the art knows the purpose of coating tablets.

The pharmaceutical composition or solid carrier particles can be coated with one or more enteric coatings, sealant coatings, film coatings, barrier coatings, compression coatings, fast-disintegrating coatings, or enzyme-degradable coatings. Multiple coatings can be applied to obtain the desired performance. In addition, one or more of the actives may be provided for immediate release, pulsatile release, controlled release, prolonged release, delayed release, targeted release, timed release, or targeted delayed release. In fact, the formulation can include combinations of typical pharmaceutical actives (for example, pseudoephedrine) and vitamins (for example, vitamin C), minerals (Ca, Mg, Zn, K) or other supplements (for example, hypericum, echinacea, amino acids ). For release / absorption control, solid carriers can be made of various types of components and levels or thicknesses of coatings, with or without an active ingredient. These various solid carriers can be mixed into a dosage form to achieve a desired performance. Liquid formulations can be administered and adapted for oral, nasal, buccal, ocular, urethral, transmucosal, vaginal, topical or rectal administration, although it is primarily used for oral administration.

When formulated with microparticles or nanoparticles, the drug release profile can easily be tailored by adding a coating, for example a hard or soft gelatin coating, a starch coating, a resin or polymer coating or a cellulosic coating. Although not limited to microparticles or nanoparticles (as in, for example, microcapsules or nanocapsules), these dosage forms can be further coated, for example, with a sealant coating, an enteric coating, a sustained release coating or a release coating. retarded directed. The term "enteric coating", as used herein, refers to a mixture of pharmaceutically acceptable excipients that is applied, combined, mixed, or otherwise added to the carrier or composition. The coating can be applied to an active that is compressed, molded or extruded and can also include gelatin or pellets, beads, granules or particles of the carrier or composition. The coating can be applied by means of an aqueous dispersion or after dissolving it in a suitable solvent. The vehicle may or may not be fully or partially biodegradable.

In one of its presentations, acrylic polymethacrylate polymers can be used as coating polymers. In at least one presentation, the coating is an acrylic resin lacquer used in the form of an aqueous dispersion, such as that commercially available from Rohm Pharma under the trade name EUDRAGIT® or from BASF under the trade name KOLLICOAT®. In the most preferred presentations, EUDRAGIT® E100 is used as the coating polymer, which is a cationic copolymer based on dimethylaminoethyl methacrylate and neutral methacrylic esters with an average molecular weight of approximately 150,000. Different coating polymers of certain presentations can be mixed in any desired ratio to ultimately obtain a coating with the desirable dissolution profile of the drug. Coating methods can consist of spraying a solution of the polymer onto the tablets, either in a coating pan or in a fluidized bed coating machine. The solvent can be organic or aqueous, depending on the nature of the polymer used. In a preferred presentation, the solvent is alcohol. Coating methods are well known in the art.

The compositions of the present invention may also be formulated as enteric coated delayed-release oral dosage forms, that is, as an oral dosage form of a pharmaceutical composition as described herein, which utilizes an enteric coating to effect delivery in the lower gastrointestinal tract. The enteric coated dosage form will generally include microparticles, microgranules, microcapsules or microbeads of the active principle or other components of the composition, which in turn are or are not coated. The enteric coated oral dosage form can also be a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or composition, which in turn are coated or not.

Carriers for use with the present invention include permeable and semipermeable matrices or polymers that control the release characteristics of the formulation. Such polymers include, for example, cellulose acylates and acetates and other semi-permeable polymers as described in US Pat.

4,285987, as well as polymers with selective permeability formed by the coprecipitation of a polycation and a polyanion as described in US patent numbers 3173876; 3276586; 3541 005; 3541 006 and 3 546 142.

Other vehicles for use with the present invention include, for example, starch, modified starch and starch derivatives, gums, including but not limited to xanthan gum, alginic acid, other alginates, bentonite, veegum, agar, guar, locust bean gum, gum arabic, quince, psyllium, flax seed, okra gum, arabinogalactin, pectin, tragacanth, scleroglycan, dextran, amylose, amylopectin, dextrin, etc., cross-linked polyvinylpyrrolidone, ion exchange resins, such as polymethacrylate potassium, derivatives), karaya gum, biosynthetic gum, etc. Other useful polymers include: polycarbonates (linear polyesters of carbonic acid); microporous materials (bisphenol, a microporous poly [vinyl chloride], microporous polyamides, microporous modacrylic copolymers, microporous acrylic styrene and their copolymers); porous polysulfones, halogenated poly (vinylidene), polychloroethers, acetal polymers, polyesters prepared by esterification of a dicarboxylic acid or anhydride with an alkylene polyol, polyalkylene sulfides, phenolic compounds, polyesters, asymmetric porous polymers, cross-linked olefinic polymers, hydrophilic microporous homopolymers, copolymers or interpolymers with a reduced bulk density and other similar materials, poly (urethane), extended cross-linked poly (urethane), poly (imides), poly (benzimidazoles), collodion, regenerated proteins, poly (vinylpyrrolidone) cross-linked semisolid.

Additional additives and their levels, and the selection of a primary coating material (s) will depend on the following properties: pH levels at the target site, convenience of making the tablet pH dependent or independent, alcohol solubility, strength to dissolution and disintegration in the stomach; impermeability to gastric fluids and drug / vehicle / enzyme while in the stomach; ability to rapidly dissolve or disintegrate at the target intestine site; physical and chemical stability during storage; no toxicity; easy application as a coating (compatible with the substrate); and economic viability.

In addition to the foregoing, various formulations are described below that illustrate the present invention, without limiting its scope. A controlled release tablet or capsule or the like comprises colchicine as a core coated with an immediate release layer. A controlled release dual layer tablet or capsule or the like comprises a sustained release layer and an immediate release layer. A controlled release tablet with more than two layers comprises (i) one or two more layers of sustained release control substance and (ii) one or two more immediate release layers.

According to one of the presentations of the invention, the composition comprising colchicine is further coated with at least one intermediate layer that slows the release of a slightly soluble intermediate layer to control the release of colchicine.

Traditionally, immediate-release dosage forms of colchicine (mainly tablets, and also injections or oral solutions) have been used in the treatment of gout or FMF. Worldwide, all approved pharmaceuticals containing colchicine are approved for gout or FMF only and are immediate-release tablets. Colchicine can be used to prevent some other inflammatory diseases such as pericarditis, PPS, and more recently, in patients with stable coronary heart disease. The difference between treatment and prevention with respect to colchicine is that in the treatment, a manifest disease or an ongoing inflammation must be treated. Therefore, high levels of colchicine are required, which generally goes hand in hand with unwanted side effects, especially gastrointestinal lesions. In prevention, it is not necessary to suppress the ongoing inflammation, but to suppress a flare-up of inflammation. Therefore, lower and more stable levels of colchicine are supposedly required, which are beneficial. As described in the present invention, this is achieved by the administration of colchicine formulated as a sustained release preparation, as described above.

In the treatment of an acute inflammatory disease such as FMF or gout, high doses and elevated serum levels are necessary and desirable to suppress inflammation. Therefore, conventional tablets with rapid release and rather low plasma half-life are suitable. However, in the case of prevention of cardiovascular disease, lower levels may be sufficient to inhibit the activity of neutrophils. The sustained release system facilitates more stable levels of colchicine and reduces the incidence of adverse reactions.

An advantage of colchicine administered as sustained release is, for example, a flattening of the curve serum level (lower but broader peak levels), which reduces the incidence of serious adverse reactions related to colchicine toxicity, also in the case of possible drug interactions. Much of the toxicity related to colchicine stems from the fact that the activity of one or both routes of excretion (liver and kidney) is reduced, either by other medications or by disease (eg, kidney failure). In the case of slower and prolonged absorption (prolonged release) of the drug, the body also has more time to excrete colchicine from the system. In this case, colchicine levels are less likely to reach toxic levels in the event of poor excretion (due to a drug interaction or disease). Furthermore, the administration of colchicine as a sustained release is resistant to the rapid discharge of the dose, therefore, the dissolution of the composition is not significantly influenced by alcohol.

Also, maintaining release increases the time that colchicine is present in the blood at therapeutic levels. Consequently, a more effective inhibition of disease progression is achieved and thus the clinical outcome is improved.

Furthermore, for the prophylactic uses described in this document, colchicine does not have to penetrate deeply into the tissue (as in gout), it can be active directly in the blood system (in the vessels), where it acts on the plaques and, on all in inflammatory blood cells (neutrophils). This means that a lower total level of colchicine and lower serum levels can be therapeutic. Rapid high levels of colchicine can be avoided, for example, as in treating an acute gout flare. Therefore, lower levels of colchicine, for example, about 0.1 to about 0.75 mg of the sustained-release formulations described above (or even less frequent doses), may be sufficient to achieve the desired clinical outcome. .

In a normal situation, most of the colchicine is absorbed in the small intestine and most of it passes into the liver (some is also excreted in the urine through the kidney). There it is metabolized, but a large proportion of colchicine passes through the liver unmetabolized. This means that it passes through the liver into the bile and from there it is excreted into the large intestine (colon). There it can be reabsorbed back into the body, leading to the characteristic second peak (it accounts for about 50% of fully absorbed colchicine and is believed to be responsible for gastrointestinal problems such as diarrhea). If colchicine is formulated as a sustained release preparation as described above, slower colchicine release results in slower reabsorption. This allows for more complete metabolization of colchicine in the liver (because at the same time it is less busy with colchicine) and therefore less recirculation of unmetabolized colchicine. Consequently, the incidence of gastrointestinal problems is reduced. Colchicine administered as sustained release according to the present invention may also be of benefit for other known side effects or adverse effects associated with the treatment or administration of colchicine (the skilled person is well aware of the adverse effects that may occur after the administration of colchicine or colchicine treatment). Thus, the administration of colchicine as a sustained release described above results in an increase and a safety advantage.

IV. Methods for the preparation of colchicine derivatives

The present invention further includes a method of preparing colchicine formulations, comprising a sustained release component and an optional immediate release component, wherein the colchicine is released from the formulation at a constant rate along the predetermined release profile. or desired.

In one of its presentations, the colchicine compositions described in the present invention are in the form of a tablet. As used herein, the term "tablet" refers to a compressed pharmaceutical dosage form in any shape or size. The tablets described herein can be obtained from compositions comprising colchicine and a pharmaceutically acceptable excipient. Any of the colchicine compositions can be presented in any other pharmaceutical form known in the art, in particular, any oral pharmaceutical form, for example, a capsule.

In a first aspect of the invention, a controlled release formulation is provided for use in oral dosage forms. The formulation includes a mixture containing hypromellose as a hydrophilic matrix, which is effective in providing a controlled release of a pharmaceutically active ingredient.

Matrix systems are well known in the industry. In a typical matrix system, the drug is homogeneously dispersed in a polymer along with conventional excipients. This mixture is normally compressed under pressure to obtain a tablet. The API is released from the tablet by diffusion and erosion. Matrix systems are described in detail in (i) Handbook of Pharmaceutical Controlled Release Technology, Ed. D. L. Wise, Marcel Dekker, Inc. New York, N.Y. (2000), and (ii) Treatise on Controlled Drug Delivery, Fundamentals, Optimization, Applications, Ed. A. Kydonieus, Marcel Dekker, Inc. New York, N.Y. (1992).

When the tablet is exposed to aqueous media, such as in the gastrointestinal tract, the surface of the tablet becomes wet and the polymer begins to partially hydrate forming an outer gel layer.

This outer gel layer is fully hydrated and begins to erode in watery liquids. Water continues to penetrate into the core of the tablet, allowing another gel layer to form under the outer gel layer that dissolves. These successive concentric gel layers maintain uniform release of API by diffusion from the gel layer and exposure by erosion of the tablet. In the case of the blends of the present invention, when included in a pressed tablet matrix, hypromellose provides a swellable hydrophilic structure capable of functioning as a gel layer. In this way the release of the drug is controlled.

According to one of the presentations, the colchicine formulation of the present invention can be manufactured by wet or dry granulation of a colchicine composition, mixing the resulting granulate with excipients and subsequently pressing the composition into tablets.

In one presentation, the wet granulation is used to prepare wet granules comprising colchicine. In the wet granulation process a granulation liquid is used. As the granulating liquid, both aqueous and non-aqueous liquids can be used. In one embodiment, the granulation liquid is an aqueous liquid, or more specifically, purified or deionized water. The amount of granulation liquid used can depend on several factors, for example, the type of granulation liquid, the amount of granulation liquid used, the type of excipient used, and the nature and charge of the active agent.

In one presentation, the colchicine particles and suitable excipients are mixed with the granulation liquid for a sufficiently long period to facilitate good distribution of all raw materials and good content uniformity. Wet granulation is generally carried out at temperatures between about 20 ° C and about 35 ° C, or more specifically, at room temperature (about 25 ° C). After wet granulation, the granulate is dried at a higher temperature to produce a dry granulate. In one of the presentations, the drying step can be carried out for a sufficiently long period until the desired residual moisture content is reached. In one of the presentations, this can be at approximately 45 ° C for around 12-48 hours. It should be noted that the total time to perform the granulation process can depend on a wide variety of factors, for example, the solvents used, the batch size, the instruments used, etc.

Any equipment can be used to contact the granulation liquid with the colchicine and excipients as long as a uniform distribution of the granulation liquid is achieved. For example, small-scale production can be achieved by mixing and moistening the colchicine and excipients in stainless steel mortars or containers, while for larger quantities, V-mixers with intensifier bars, planetary mixers, rotary granulators, granulators can be used. high shear and fluidized bed granulators. In one presentation, the granulator is a high-shear granulator.

In one of the presentations, a method for preparing a colchicine composition consists of wet granulating the colchicine with pharmaceutically acceptable excipients and a granulating liquid to obtain wet granules, and mixing the granules in the next step with a second excipient to obtain a composition of colchicine. In one embodiment, the pharmaceutically acceptable carrier comprises a binder and a diluent. In one of the presentations, the binder can be hypromellose. In one of the presentations, the diluent can be lactose monohydrate and pregelatinized starch. In another presentation, purified water is used as the granulation liquid. In one of the presentations, the second excipient mixed with the granules can be a diluent. In one of the presentations, the diluent can be lactose monohydrate. Colchicine compositions may contain about 0.1% to about 10% by weight, or more specifically, from about 0.25% to about 0.75% by weight, in colchicine, based on the total weight of the colchicine composition. colchicine.

In one of the presentations, a method for preparing a composition consists of wet granulating the colchicine with a pharmaceutically acceptable excipient to obtain wet granules, and mixing the granules with a diluent to obtain a colchicine composition. In some presentations, the method also includes drying the mixture. In another presentation, the wet granules are dried to obtain dry granules and, subsequently, the dry granules are mixed with a binder, a diluent or both to obtain the composition. In another embodiment, the dry granules can be crushed into crushed granules before mixing the crushed dry granules with the binder, a diluent, or both. The method may also involve mixing the colchicine composition with a glidant, a lubricant or both to obtain a mixture or compressing the mixture to obtain a tablet. In one of the presentations, the slipper can be talc. In another presentation, the lubricant can be stearic acid. The method can also involve coating the tablet.

In another embodiment, a method of preparing a colchicine tablet involves wet granulating the colchicine with a pharmaceutically acceptable excipient to obtain wet granules; drying the wet granules to obtain dry granules; grinding the dry granules to obtain crushed granules; mixing the crushed granules with a diluent to obtain the composition; mixing the composition with a slipper, a lubricant or both to obtain a mixture; and compress the mixture to obtain a colchicine tablet from the present invention.

In some presentations, the wet granules are dried to obtain dry granules before being mixed with a second excipient, for example, a diluent. The wet granules can be dried by any suitable means to remove the granulation liquid and form dry granules containing colchicine and the pharmaceutically acceptable excipient. The conditions and duration of drying depend on factors such as the liquid used and the weight of the granulation particles. Examples of suitable drying methods include, for example, tray drying, forced air drying, microwave drying, vacuum drying and fluid bed drying.

After drying, the dried granules can be mixed directly with an excipient, for example a diluent, a binder or a lubricant, for further processing. Alternatively, the dried granules may optionally undergo additional processing steps prior to mixing with the excipient. For example, dry granules can be sized to reduce particle size prior to mixing with an excipient. Some examples of sizing operations are crushing or sieving. Any suitable equipment to reduce particle size can be used in the present invention.

Suitable excipients can be added extra-granularly and mixed with the granules to form colchicine compositions. As used herein, the term "extragranular" or "extragranularly" means that the reference material, eg a suitable excipient, is added or has been added as a dry component after granulation. wet. In one form, a diluent, binder, glidant, and lubricant are added extra-granularly to the granules and integrated to form a mixture. The mixture can be encapsulated directly in capsule shells, for example hard gelatin shells, to form capsule formulations. Alternatively, the mixture can be compressed into tablets. In some presentations, the granules are dry granules or crushed dry granules.

Mixing can be carried out for a time sufficient to produce homogeneous mixtures or blends. Mixing can be accomplished by blending, hardening, stirring, drum mixing, rolling, or by any other method that allows for a homogeneous mix. In some presentations, the components to be mixed are combined under low shear conditions in a suitable apparatus, such as a V-mixer, bin mixer, double cone mixer, or any other apparatus capable of operating under low shear conditions. .

The homogeneous blends or blends are subsequently compressed by any suitable method in the industry. The mechanical force will define the physical properties of the tablets, especially the compressive strength of the resulting tablet. Mechanical strength interacts with the initial swelling of the tablet and the dilution rate of the tablet core. This effect is well known in the art and can be adjusted and controlled during the life cycle of the product. For the sustained-release colchicine formulation of the present invention, the compressive strengths used may range from approximately 30N to approximately 130N. In one form, the compressive strength may be approximately 100N. In another. of the presentations, the compressive strength can be approximately 100 N / -15 N.

Colchicine tablets prepared from the methods described above show acceptable physical characteristics including good friability and hardness. According to the guidelines of the European (EP) and United States (USP) Pharmacopoeias, the colchicine tablets described herein have a friability ranging from about 0% to less than about 1%.

The colchicine tablet can be coated. Tablet coating can be done by any known process. A coating for the colchicine tablet described herein can be any suitable coating, for example, a functional or non-functional coating, or multiple functional or non-functional coatings. By "functional coating" is meant to include a coating that modifies the release properties of the total formulation, eg, a sustained release coating. By "non-functional coating" is meant to include a coating that is not a functional coating, eg, a cosmetic coating. A non-functional coating may have some impact on the release of the active ingredient due to initial dissolution, hydration, perforation of the coating, etc., but a significant deviation from the uncoated composition would not be considered.

In one embodiment, a colchicine composition comprises colchicine, a binder, a diluent, a retarding agent, a slipper, and a lubricant. In one presentation, a colchicine composition comprises about 0.25 to about 0.75 mg of colchicine; from about 10 to about 80 mg of lactose monohydrate; from about 5 to about 50 mg of pregelatinized starch; from about 1 to about 30 mg of 6 mPa * s hypromellose; from about 5 to about 40 mg of Retalac (compound of lactose monohydrate and hypromellose of 4000 mPa * s 50/50% ph); from about 0.5 to about 5 mg of talc; and from about 0.5 to about 5 mg of stearic acid 50. In one embodiment, the colchicine composition comprises about 0.5 mg of colchicine; about 59 mg of lactose monohydrate; about 7.5 mg of pregelatinized starch; about 1 mg of 6 mPa * s hypromellose; about 30 mg of Retalac (compound of lactose monohydrate and hypromellose of 4000 mPa * s 50/50% ph); about 1 mg of talc; and about 1 mg of stearic acid 50. The pharmaceutical form of colchicine has a total weight of about 100 mg. The composition of the colchicine may be in the form of a tablet.

V. Methods of treatment using sustained-release colchicine

The present invention also features a method of treating or preventing cardiovascular disease or inflammatory disorders in a subject, including administering to the subject a therapeutically effective amount of a colchicine formulation of the present invention, wherein the colchicine is released from the formulation. at a constant rate along a predetermined or desired release profile. The method of the present invention possesses the flexibility to selectively adjust the pharmacokinetics of the administered formulations depending on the nature of the disease and the needs of the patients due to the new design of the colchicine formulation, which consists of a prolonged release component. and an optional immediate release, and the release profiles of both components can be selectively modified during the preparation process as described above to meet the predetermined release profile.

In one embodiment, treatment includes applying or administering a colchicine formulation to a patient as described herein, because the patient suffers from or is at risk of developing a cardiovascular disease or an inflammatory disorder. In another of the presentations, the treatment also envisages including the application or administration of a pharmaceutical composition containing a colchicine formulation to a patient, because the patient suffers from or is at risk of developing a cardiovascular disease or an inflammatory disorder.

As used herein, the term "cardiovascular disease" refers to any disease that affects the heart or vascular system (all blood vessels, including arteries, capillaries, and veins). This includes all the diseases listed in Chapter IX "Diseases of the circulatory system (100-199)" of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10), version 2010, of the World Organization Of the health.

Specifically, all ICD-10 diseases of this class that involve a) inflammation of any part of the heart or blood vessel, as well as b) ischemia / atherosclerosis / thickening of any blood vessel of the circulatory system.

Colchicine, as described herein, is used in the treatment or prevention of any inflammatory disorder involving cardiac tissue selected from ICD-10 sections 100-199. Specifically, these disorders include acute and recurrent pericarditis, as well as postsurgical complications involving inflammation of the pericardium (postcardiotomy syndrome, postpericardiotomy syndrome, pericardial effusion). Other covered inflammatory heart diseases are any form of myocarditis, endocarditis, and atrial fibrillation.

The mechanism of action proposed in this indication is the inhibition of plaque instability by inhibition of neutrophils. In stable coronary artery disease, fatty materials accumulate in the blood vessels and form a stable plaque. This plaque can be attacked by neutrophils, which can cause plaque instability and consequently lead to plaque rupture and clinical events. Therefore, colchicine, as described in this document, is used in the treatment or prevention of any disease of the cardiovascular system involving ischemia, atherosclerosis or thickening of the blood vessels (arteries, capillaries, veins) due to the formation of plaque with risk of clinical events due to plaque instability. All diseases classified in section 100-199 of the ICD-10 that meet any of these requirements are declared. Examples include stable coronary artery disease, cardiovascular atherosclerosis and peripheral vascular system atherosclerosis, abdominal aortic aneurysm (AAA), and carotid and iliofemoral / renal atheromas (eg, 125,170).

In the context of the present invention, an acute cardiovascular event in a patient with stable cardiovascular disease is preferably a cardiovascular event in a patient with stable coronary disease. In the context of the present invention, the term "stable coronary disease" and "stable coronary heart disease" have the same meaning and are used interchangeably. Both terms include the condition "stable coronary artery disease" (SCAD). "Stable" in the context of the terms "stable cardiovascular disease", "stable coronary disease" or "stable coronary heart disease" is defined as any state of cardiovascular disease diagnosed in the absence of acute cardiovascular events. Therefore, for example, stable coronary disease defines the different evolutionary phases of coronary disease, excluding situations in which coronary artery thrombosis dominates the clinical presentation (acute coronary syndrome).

In the context of the present invention, colchicine can be used for the prevention or treatment of cardiovascular diseases. Cardiovascular diseases include, but are not limited to, the heart diseases described, for example, in Robbins and Cotran, Pathologic Basis of Disease, Eighth Edition, Saunders Elsevier. Cardiovascular disease refers to a group of diseases of the circulatory system that includes the heart, blood and lymphatic vessels. In particular, cardiovascular disease can include vascular diseases involving atherosclerosis and plaque formation or removal. The most common cardiovascular diseases are coronary heart disease and stroke. Some non-limiting examples of cardiovascular diseases that can be prevented or treated according to the methods of the invention include coronary heart disease (disease of the blood vessels supplying the myocardium), cerebrovascular disease (disease of the blood vessels supplying the brain). ), peripheral arterial disease (disease of the blood vessels supplying the arms and legs), rheumatic heart disease (damage to the myocardium and heart valves due to rheumatic fever, caused by streptococcal bacteria), congenital heart disease (malformations of the cardiac structure existing at birth), deep vein thrombosis and pulmonary embolism (blood clots in the veins of the legs, which can dislodge and travel to the heart and lungs), hyperlipidaemia (an excessive level of fats in the blood, such as LDL ), high blood pressure, coronary artery disease, atherosclerosis, ischemic diseases, aneuris abdominal aortic ma, carotid and iliofemoral / renal atheromas, heart failure, heart rhythm disorders, arteriosclerosis, myocardial infarction and stroke. Myocardial infarctions and strokes are usually acute events and their cause is mainly a blockage that prevents blood from flowing to the heart or brain. The most common reason for this is the accumulation of fatty deposits on the inner walls of the blood vessels that supply the heart or brain. Strokes can also be caused by bleeding from a blood vessel in the brain or by blood clots.

Above all, in the context of the present invention, colchicine can be used for the prevention of acute pericarditis, recurrent pericarditis, recurrent pericarditis in patients with a history of pericarditis, post-pericardiotomy syndrome (PPS), PPS in patients undergoing cardiac surgery and Cardiovascular events in patients with stable coronary (heart) disease (cardiovascular events may be acute cardiovascular events).

Pericarditis is an inflammatory disease that affects the pericardium, a thin, double-walled fibroelastic sac that surrounds the heart. Due to inflammation, the pericardium becomes irritated and swollen, causing the sac to rub against the heart, causing chest pain, the most common symptom of pericarditis. Pericarditis is the most common form of inflammatory heart disorder, although it is very rare in the population. Pericarditis is very heterogeneous in its origin, clinical manifestations, and duration of symptoms. It can occur as an isolated clinical problem or as a manifestation of a systemic disease. In most cases (90%), pericarditis is of idiopathic etiology (spontaneous, unknown), but it can also be secondary to systemic infections, acute myocardial infarction, or autoimmune diseases. Postpericardiotomy syndrome (PPS) can be a troublesome complication after heart surgery, occurring anywhere from a few days to several weeks after surgery. The estimated incidence of the syndrome has a relatively wide range, affecting 10% to 40% of patients undergoing cardiac surgery (Prince and Cunhe, 1997, Heart Lung, 26: 165).

Some non-limiting examples of (acute) cardiovascular events are atherosclerotic wall injury, acute coronary syndrome, out-of-hospital cardiac arrest, or non-cardioembolic ischemic stroke. Other such episodes are described, for example, in Robbins and Cotran, Pathologic Basis of Disease, Eighth Edition, Saunders Elsevier.

In one of the presentations, the colchicine formulation of the present invention can be used to treat inflammatory diseases other than those mentioned above. In one of the presentations, they are included as inflammatory diseases, for example, gout, familial Mediterranean fever, Behget's disease, age-related macular degeneration and Alzheimer's disease.

Patients / subjects, suffering from the disease described above or suitable for colchicine treatment according to the present invention, can be diagnosed by conventional or routine procedures. An expert in the field knows them well. Other such diagnoses are also described, for example, in Robbins and Cotran, Pathologic Basis of Disease, Eighth Edition, Saunders Elsevier.

In one of the presentations, the colchicine formulation described herein is useful for the treatment of various cardiovascular diseases or inflammatory disorders. In some presentations, the treatment of a cardiovascular disease or inflammatory disorder is intended to include remediation, amelioration, amelioration, amelioration of the severity or reduction of the time course of a disease, disorder or condition, or any of its parameters or symptoms. In one of the presentations of the present invention, the term "disorder", "disease" or "condition" is to be understood as a cardiovascular disease or an inflammatory disorder, as described above. In the context of the present invention, "alleviation" refers, inter alia, to any observable beneficial effect.

In accordance with the present invention, the colchicine formulation herein can be used to promote a positive therapeutic response with respect to cardiovascular disease or inflammatory disorder. A 'positive therapeutic response' to cardiovascular disease or inflammatory disorder is intended to include an improvement in disease that can be corroborated, for example, by a delay in onset of the clinical symptoms of the disease or condition, a reduction in the severity of some or all of the clinical symptoms of the disease or condition, a slower progression of the disease or condition, an improvement in the general health or well-being of the subject, or by other parameters well known in the art that are specific to this particular disease.

In another presentation, the colchicine formulation described herein is useful for the prevention of various cardiovascular diseases or inflammatory disorders. In the context of the present invention, the term "prevention" is well known in the art. For example, a patient / subject suspected of being prone to a disorder or disease as defined herein may, in particular, benefit from a prevention of the disorder or disease. The subject / patient may have a susceptibility or predisposition to a disorder or disease, including, for example, a hereditary predisposition. Such predisposition can be determined by standard assays, using, for example, genetic markers or phenotypic indicators. It is understood that a disorder or disease that can be prevented in accordance with the present invention has not been diagnosed or cannot be diagnosed in the patient / subject (eg, the patient / subject does not show any clinical or pathological symptoms). Therefore, the term "prevention" encompasses the use of compounds of the present invention before any clinical or pathological symptoms are diagnosed or determined or can be diagnosed or determined by the treating physician. Prevention includes, but is not limited to, preventing the disease or condition from appearing in the patient or subject who may be predisposed to the disease but is not yet experiencing or showing symptoms of the disease (prophylactic treatment).

In accordance with the present invention, colchicine can also be used in combination with conventional treatment for any of the diseases described herein. These conventional treatments are well known in the art and such treatments are known to the person skilled in the art. Colchicine, as described herein, can also be used in combination with statins compatible with colchicine. In general, some examples of statins are atorvastatin (Lipitor®, Torvast®), fluvastatin (Lescol®), lovastatin (Mevacor®, Altocor®, Altoprev®), pitavastatin (Livalo®, Pitava®), pravastatin (Pravachol®, Selektine ®, Lipostat®), rosuvastatin (Crestor®) and simvastatin (Zocor®, Lipex®). In connection with the present invention, colchicine compatible statins are used. Preferably, in the context of the present invention, the combination of the composition of the present invention with statins compatible with colchicine is achieved in connection with stable coronary heart disease. These statins are preferably statins which, due to the nature of their mechanism of action, metabolization or clearance do not, or only to a small extent, interfere with the mechanism of action, metabolization or clearance of colchicine and therefore show a lower risk, severity or incidence of drug-related adverse reactions when administered in combination with colchicine.

In one of the presentations, the use of colchicine is in fixed combination (within the same pharmaceutical preparation) or non-fixed (different pharmaceutical preparation). By "fixed combination" is meant a combination whose active ingredients are combined in fixed doses in the same vehicle (single formula) that administers them together at the point of application. The fixed combination can mean, for example, a single tablet, solution, cream, capsule, gel, ointment, ointment, patch, suppository or transdermal delivery system. A 'non-fixed combination', as used herein, means that the active ingredients or ingredients are in more than one vehicle (eg, tablets, solutions, creams, capsules, gels, ointments, ointments, patches, suppositories, or systems. transdermal administration). Each of the carriers can contain a pharmaceutical composition or a desired active component. For example, a preferred non-fixed combination, as described herein, means that one vehicle contains colchicine, as described herein, and another vehicle contains a colchicine-compatible statin, as described herein. Examples of colchicine described herein in fixed or non-fixed combinations comprise colchicine in combination with one or more colchicine compatible statins selected from the group consisting of atorvastatin, rosuvastatin, simvastatin and pravastatin. In particular, the colchicine described herein in fixed or non-fixed combination is to be understood as colchicine in combination with atorvastatin. In particular, the colchicine described herein in fixed or non-fixed combination is to be understood as colchicine in combination with rosuvastatin. In particular, the colchicine described herein in fixed or non-fixed combination is to be understood as colchicine in combination with simvastatin. In particular, the colchicine described herein in fixed or non-fixed combination is to be understood as colchicine in combination with pravastatin.

In some forms, colchicine, as described herein, can be used in combination with a statin and another agent, such as ezetimibe / simvastatin. Colchicine, as described herein, can be used in combination with other drugs, for example, which are used in medicine and are known to the expert (for example, antibiotics, NSAIDs [non-steroidal anti-inflammatory drugs], corticosteroids) .

SAW. Administration methods

Methods for preparing and administering the colchicine formulation of the present invention to a subject in need thereof are well known or readily determined by those skilled in the art. The route of administration of the colchicine formulation can be, for example, oral, parenteral, inhalational or topical. The term parenteral, as used herein includes, for example, intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, rectal or vaginal administration.

Colchicine, when used as a composition in the context of the present invention, can include one or more pharmaceutically acceptable carriers and can therefore be prepared as a local formulation, so that it can be administered. The pharmaceutically acceptable carrier may include a saline solution, sterile water, persistent liquid, saline buffer, a dextrose solution, a maltodextrin solution, glycerol, ethanol, and mixtures of one or more thereof, and may also include an additive such as a antioxidant, a buffer, a bacteriostatic agent, or the like, as needed. Also, a diluent, a dispersant, a surfactant, a binder and a lubricant can be added when preparing the composition according to the present invention, for example, in the form of a local formulation such as an ointment, lotion, cream, gel, emulsion. skin, skin suspension, patch or spray.

Some examples, without limitation, for the administration of the compound or compositions according to the present invention include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, lozenges, pills, solutions, emulsions, suspensions, syrups, elixirs. , powders and granules to reconstitute, dispersible powders and granules, medicinal gum, chewable tablets and effervescent tablets. The composition according to the present invention can be administered in any pharmaceutical form for administration orally (for example, solid, semisolid, liquid), dermal (for example, dermal patch), sublingual, parenteral (for example, injection), ophthalmic (for example, eye drops, gel or ointment) or rectal (for example, suppositories). In one presentation, the composition is formulated as a tablet, capsule, suppository, skin patch, or sublingual formulation.

The pharmaceutical compositions used in this invention comprise pharmaceutically acceptable carriers, including, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin; buffer substances such as phosphates; glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate; Disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyethylene-polyoxypropylene block polymers and lanolin.

Some pharmaceutical compositions used in this invention can be administered orally in an acceptable dosage form including, for example, capsules, tablets, and aqueous solutions or suspensions. Certain pharmaceutical compositions can also be administered by nasal spray or inhalation. Said compositions can be prepared as solutions in saline solution, using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability or other conventional solubilizing or dispersing agents.

The amount of colchicine formulation that must be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. The composition can be administered as a single dose, multiple doses, or over a set period of time in an infusion. Dosages can also be adjusted to provide the optimal desired response (eg, a therapeutic or prophylactic response).

In some situations, the composition of the present invention can be administered parenterally. Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous vehicles include, for example, water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. In the present invention, pharmaceutically acceptable carriers include, but are not limited to, a 0.01-0.1 M phosphate buffer, and preferably 0.05 M or a 0.8% saline solution. Other common parenteral vehicles include sodium phosphate solutions, Ringer's dextrose, sodium chloride dextrose, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, and electrolyte replenishers, such as those based on Ringer's dextrose and the like. They may also contain preservatives and other additives such as antimicrobials, antioxidants, chelating agents and inert gases and the like.

Parenteral formulations can be a single bolus dose, an infusion, or a bolus loading dose followed by a maintenance dose. These compositions can be administered at specific fixed or variable intervals, for example, once a day or as needed.

The composition, according to the present invention, can be administered in a dose range that varies as a function of body weight, age, sex, health status, diet, time of administration, method of administration, rate of excretion and severity of the patient's disease. The compounds of the present invention as compounds per se in their use as pharmacophores or as pharmaceutical compositions can be administered to the patient or subject in a suitable dose. The dosage will be determined by the treating physician and clinical factors. As is well known in the medicinal arts, the doses for any patient depend on many factors, including the patient's body size, body surface area, age, specific compound to be administered, sex, time and route of administration, general health, and other medications administered at the same time. Generally, the dosage as a regular administration of the pharmaceutical composition comprising what is defined herein should be, for example, in one of the ranges described below. Progress can be monitored through regular evaluations.

The composition according to the present invention can be administered as a single dose or with 2, 3, 4, 5, 6, 7, 8, 9 or 10 doses, if desired. The composition can be administered 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times a day. Preferably, the colchicine according to the present invention is administered once a day. Preferably, the colchicine according to the present invention is administered once a day as a single dose.

The composition according to the present invention can be administered regularly for long periods of time. In one of the presentations, the composition can be administered regularly for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more years. In another embodiment, the composition can be administered regularly for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more months. In other presentations, the composition can be administered regularly for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more weeks. As used herein, the term "regularly" refers to the administration of the composition at regular hours or intervals over a period of time. For example, the composition can be administered to a patient once a day for three years. In other presentations, the composition can be administered to a patient once every other day for 5 years. It should be noted that the frequency of administration may vary depending on a number of factors, including, but not limited to, the severity of the disease, the general health of the patient, any additional medications the patient is taking, and whether or not the treatment is prophylactic or not. It should also be appreciated that the frequency of administration can be adjusted at any time.

The amount / concentration / dose of the composition according to the present invention may be between 0.1 mg and 5.0 mg, 0.1 mg and 2.0 mg, 0.1 mg to 1.5 mg, 0.1 mg to 1.0 mg, 0.1 mg to 0.75 mg, 0.1 mg to 0.5 mg, 0.25 mg to 5.0 mg, 0.25 mg to 2.0 mg, 0.25 mg to 1.5 mg, 0.25 mg to 1.0 mg, 0.25 mg to 0.75 mg, or 0.25 mg to 0.5 mg. In one of the presentations, the composition according to the present invention is administered in a daily dose of colchicine of between about 0.1 mg and about 0.75 mg or between about 0.1 mg and about 0.5 mg. In another embodiment, the composition according to the present invention is administered in a daily dose of colchicine of between about 0.25 mg and about 0.75 mg or between about 0.25 mg and about 0.5 mg. In one of the presentations, the composition according to the present invention is administered in a daily dose of approximately 0.5 mg of colchicine.

In a preferred presentation, the amount / concentration of colchicine, used herein, can be administered on the first day of administration in a higher dose (concentration / amount) compared to the administration of colchicine on the following days of administration. (maintenance administration / maintenance administration dose). Alternatively, this reduced dose (maintenance dose) can be started 2, 3, 4, 5, 6, 7, 8, 9 or 10 days after the initial administration of the highest dose. In case the treatment plan is as described above, the highest dose / amount / concentration of colchicine (for example, on the first day of administration) can be any of those described above, as long as the maintenance dose ( the dose / amount / concentration of colchicine in the days following the highest dose / amount / concentration) is less than the initial dose / amount / concentration of colchicine (for example, on the first day of administration). Preferably, the composition of the invention is administered with a dose of colchicine comprised between about 1.0 mg and about 2.0 mg on the first day (preferably as a single dose) of administration and the maintenance dose of colchicine on the following days. Administration is between about 0.5 mg and about 1.0 mg.

Within the scope of the present disclosure, the colchicine formulation of the present invention can be administered to a human or other animal according to the aforementioned treatment methods in an amount sufficient to produce a therapeutic effect. The colchicine formulation can be administered to such human or other animal in a conventional pharmaceutical form prepared by combining the colchicine formulation of the invention with a conventional pharmaceutically acceptable carrier or diluent according to known techniques. One skilled in the art will recognize that the form and nature of the pharmaceutically acceptable carrier or diluent are determined by the amount of the active ingredient with which it is to be combined, the route of administration, and other well-known variables.

By "therapeutically effective dose or amount" or "effective amount" is meant an amount of the colchicine formulation which, when administered, produces a positive therapeutic response with respect to the treatment of a patient with a disease to be treated, specifically , an improvement in the disease that can be corroborated, for example, by a delay in the onset of the clinical symptoms of the disease or condition, a reduction in the severity of some or all of the clinical symptoms of the disease or condition, an advance slower of the disease or condition, an improvement in the general health or well-being of the subject, or by other parameters well known in the art that are specific to this particular disease.

The invention also provides for the formulation of colchicine in the manufacture of a medicament for treating a subject. of a cardiovascular disease or an inflammatory disorder, in which the medicament is used in a subject who has been pretreated or is being treated simultaneously with at least one other treatment. By "pretreatment" or "pretreatment" it is meant that the subject has received one or more treatments prior to receiving the medicament comprising the colchicine formulation. "Pretreatment" or "pretreatment" includes subjects who have been treated with at least one other treatment within a period of 2 years, 18 months, 1 year, 6 months, 2 months, 6 weeks, 1 month, 4 weeks, within 3 weeks, 2 weeks, 1 week, 6 days, 5 days, 4 days, 3 days, 2 days or even 1 day before the start of treatment with the drug comprising the colchicine formulation. By "simultaneous" or "concomitant" it is meant that the subject has received one or more treatments at the same time as receiving the drug comprising the colchicine formulation. It is not necessary for the subject to have responded to the pretreatment with the previous treatment (s) or to have responded to the concomitant treatment (s). Thus, the subject receiving the drug comprising the colchicine formulation could have responded, or might not have responded, to the pretreatment with the prior therapy, or to one or more of the prior therapies in which the pretreatment comprised multiple treatments.

EXAMPLES

Example 1: Sustained-release colchicine tablet

This example illustrates a sustained release colchicine tablet. The tablet uses the principles and concentrations shown in Table 1 below.

The concentrations can be modified to change certain properties of the formulations, for example, the dissolution profile. Table 2 shows the ranges for each principle.

Example 2: Method of making a sustained-release colchicine tablet

The above ingredients are used to make a tablet with the following working instructions:

Granulation: Granulation was done in a Kenwood mixer. Colchicine and 6 Mpa * s hypromellose are they were weighed first and dissolved separately in purified water. This 6 MPa * s hypromellose solution was loaded into the lactose-containing mixer in 1.5 min followed by a 3 minute mixing time. Subsequently, the dissolved colchicine was sprayed with a diluent (eg, lactose monohydrate) in continuous mixing for a period of 15 minutes. These steps were carried out at room temperature. Subsequently, the wet granulate was passed through a 1.0 mm manual sieve. It was then dried in an oven (Haeraeus) at 45 ° C for 26 h until reaching a residual moisture content of 0.53%, and passed through a 0.8 mm sieve (Erweka AR 400). Density parameters (Engelmann) were tested. Bulk density 0.53 g / ml, compacted bulk density 0.67 g / ml, Hausner ratio 1.26. Rheology: 4 second flow time; 23.8 ° tilt angle.

Mixing: After the granulation process, the granulate is combined with a diluent (for example, lactose monohydrate), a retarding agent (for example, Retalac) and other excipients (for example, flow enhancer, glidants or lubricants) to support the tablet compression process. For this, these ingredients were manually passed through a 0.8 mm sieve and mixed with the granulate in a bucket mixer (Erweka) for 10 minutes. In one of the presentations, the slipper used can be talc. In another presentation, the lubricants used can be stearic acid. The granules are then mixed by means of a suitable mixer.

Tablet compression: compressing force is required to form tablets. The mechanical force will define the physical properties of the tablets, especially the compressive strength of the resulting tablet. Mechanical strength interacts with the initial swelling of the tablet and the dilution rate of the tablet core. This effect is well known in the art and can be adjusted and controlled during the life cycle of the product.

Tableting was performed on a Korsch (EK 0) tablet press with a 6 mm diameter, biconvex, round tableting tool. The average hardness of the tablets was approximately 100 N / -15 N. The tablets were approximately 100 mg in mass; friability was not measurable. The breaking strength and hardness were measured with an Erweka Multickeck. Friability was measured with an Erweka Friabilator and a Mettler analytical balance. Dimensions were measured using a Mitutoyo caliper.

Example 3: Measurements of dissolution profiles of sustained release colchicine formulations

The dissolution of the sustained release colchicine formulation was measured at various time points. The compositions were dissolved in 500 ml of water at 37 ° C and continuously stirred for a period of 6 hours. Samples were drawn at various times to study the kinetics of the drug dissolution process within the hydrophilic matrix system. The colchicine content in the samples was analyzed by HPLC analysis.

Several batches were tested to determine the optimal dissolution profile for the sustained release formulation. Release can be modified both by the concentration of hypromellose and by the use of different viscosity grades of hypromellose (eg 1000 mPa or 10,000 mPa). In the batches tested below, the viscosity grade remained constant, however, the hypromellose concentration of 4000 mPa in the tablet was changed.

Table 3 below summarizes the various compositions tested.

The dissolution profiles of the various batches are provided in Tables 4-6 and Figures 1-4. Specifically, the dissolution profile for Batches 1-3 is summarized in Table 4 and Figure 1. The profile for Lot 1 shows approximately a 92% release in about 30 minutes, followed by a constant release. Complete dissolution occurred after 2 hours. Lot 2 shows approximately 83% release in about 30 minutes, ^{followed by steady release. Complete dissolution occurred after 2 hours. Lot 3 shows} approximately a 74% release in about 30 minutes, followed by a steady release. Complete dissolution occurred after 2 hours.

^{The dissolution profile for Lot 4 is summarized in Table 5 and Figure 2. Lot 4A shows approximately a} 30% release in about 30 minutes, followed by a constant release. Complete dissolution occurred after 6 hours. Lot 4B shows approximately a 23% release in about 30 minutes, followed by a steady release. Complete dissolution occurred within 6 hours. In this example, a difference in tablet hardness results in a difference in release rates. ^{Figure 3 shows the dissolution profiles for lots 1-4.}

The dissolution profile for Lot 5 is summarized in Table 6 and Figure 4. Lot 6 represents the immediate release version of the composition. The profile for Lot 5 shows a 90% release in a 5 minute period. ^{Complete dissolution occurred within 2 hours.}

As mentioned above, the release profile of the sustained release composition can be changed to a specific or desired target release by adjusting the amount of retarding agent (ie Retalac) as well as the hardness of the tablet. Release is dependent on several factors, including erosion of the outer colchicine layer (ie, the rate of immediate release), as well as diffusion of the inner colchicine layer (ie, the rate of sustained release). Since the percentage of colchicine is low in the sustained release formulation and the tablets are small, this balance between erosion and diffusion is very sensitive and must be adjusted to achieve a very specific dissolution profile.

Example 4: Measurements of dissolution profiles of sustained-release colchicine formulations in ethanol

To evaluate the potential for rapid release of the dose, or dissolution of the composition in alcohol, the dissolution of the sustained-release formulation of colchicine in ethanol was measured at various times. The compositions were dissolved in 500 ml of three 5%, 20% and 40% ethanol solutions at 37 ° C and continuously stirred for a period of 6 hours. Samples were drawn at various times to study the kinetics of the drug dissolution process within the hydrophilic matrix system. The colchicine content in the samples was analyzed by HPLC analysis.

Example 5: Therapeutic Effects of Sustained Release Colchicine Formulations

The therapeutic effect of the sustained-release formulation containing colchicine is evaluated in a clinical study which is a multi-dose, randomized, crossover study that will evaluate the bioavailability of approximately 3 different 0.5 mg sustained-release formulations (for example , test product 1, 2, 3) of colchicine with an immediate release formulation of 0.5 mg (control product), administered to healthy volunteers. The main objective of the study is to evaluate the pharmacokinetics (PK) of the test and control drug in blood, as well as in neutrophils or leukocytes.

Research Objective: The primary objective of this study is to compare the pharmacokinetics of the test product versus the colchicine control product in healthy human volunteers. In particular, the levels of colchicine in blood (referred to herein as blood PK), neutrophils or leukocytes (referred to herein as neutrophil PK) will be assessed after treatment with the test and control product.

The proven hypothesis is that the administration of an equal amount of colchicine in sustained-release tablet form results in lower peak levels (Cmax), while maintaining the same absolute bioavailability (area under the curve, AUC). Colchicine concentrations in neutrophils are measured because it is generally recognized that neutrophils that reconstitute 60-70% of leukocytes play a central role in inflammatory responses in general and are believed to be the major players in various diseases in those in which colchicine is used as a treatment. Therefore, for the purpose of this experiment, both leukocytes and neutrophils can be analyzed. Accordingly, the term neutrophils used herein also refers, if used, to leukocytes. As colchicine is known to preferentially accumulate in neutrophils and inhibit many of their pro-inflammatory functions, they are believed to be a primary target of colchicine treatment. Therefore, it is of special interest to know whether similar concentrations of colchicine are achieved in neutrophils or in isolated leukocytes, which would give information on potential bioequivalence. So blood will be drawn at various times throughout the study to check blood levels of colchicine and neutrophils.

General Study Design: This study has been designed as a randomized crossover study. There will be 3 groups of patients (n = 3x at least 8). Group 1 will receive the control or test drug for about 8-14 days. After a washout period, they will receive Test Drug 1 for approximately 8-14 days. Group 2 will receive the controller medicine for the same time. After a washout period, they will receive Test Drug 2 for the same time. Group 3 will receive the controller medicine for the same time. After a washout period, they will receive Test Drug 3 for the same time. Study participants receive inpatient treatment for the first 24 hours and on an outpatient basis for the remaining time. There is a sufficiently long wash-out period between the two tests.

Participation of the subjects: there will be 3 groups of patients (n = 3x at least 8). For each test drug, healthy volunteers will be randomly assigned to a drug for the first round. After a long enough washout period, the same subjects will receive the control drug.

Study Duration: Study drug is administered as a single dose / day for approximately 8-14 consecutive days. The study consists of 24 h blood PK (high frequency data collection). The PK in neutrophils is analyzed at intervals that allow the colchicine levels in them to be conclusively determined during the experiment.

Dosing regimen: Below is an example of what the dosing regimen can look like.

Research techniques and data analysis: analytical chemistry techniques (HPLC) or immunological techniques (radioimmunoassay) can be used for the evaluation of colchicine and, optionally, its metabolites. The collected data is analyzed using appropriate statistics and data management software.

Study population: the study population consists of healthy male volunteers. To be included in the study, the patient must be between 25 and 40 years old; not less than 60 kg and not more than 120 kg of body weight; be healthy; no major concurrent comorbidities or contraindications to colchicine treatment; be willing to consent and be randomized into the study. Patients who meet the following criteria will be excluded: ongoing treatment with other anti-inflammatory / immunosuppressive drugs; drug treatment with known drug interactions with colchicine; kidney / liver failure; known hypersensitivity to colchicine.

Treatment scheme: the drug is administered once a day in the morning.

Data Collection Scheme: For blood PK, blood will be collected over a 24 hour period at the start of the study at short intervals (sufficient time points to establish pharmacokinetic data, for example: -1, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h, 15 h and 24 h (before next application). Additional time points can be 24 h and 72 h after drug withdrawal at the end of study to examine drug washout phase Pk analysis includes blood colchicine concentrations Appropriate techniques are applied for blood isolation and colchicine quantification.

For neutrophil PK, neutrophils will be isolated or purified from raw blood at various time points. Neutrophils will be collected at the start of the study, as well as at least once at the end of the study. The PK analysis includes colchicine concentrations in isolated neutrophils.

Example 6: Therapeutic effects of an immediate release formulation in patients with cardiovascular disease

To evaluate the therapeutic effects of an immediate-release formulation in patients with cardiovascular disease, a prospective, randomized, observer-blind end-point trial was conducted to determine whether adding 0.5 mg / day of colchicine to treatments Secondary prevention standards that include aspirin and high-dose statins reduce the risk of cardiovascular events in patients with clinically stable and objectively diagnosed coronary disease. This study is described in PCT / AU2013 / 001261 and is incorporated herein in its entirety by reference.

Study conduct and design: The LoDoCo (low-dose colchicine) trial was conducted under the supervision of the Heart Research Institute of Western Australia. It was designed by leading investigators, registered in the Australian Clinical Trials Registry (12610000293066), and received ethical approval from the Human Research Ethics Committee at Sir Charles Gairdner Hospital, Perth, Western Australia, in July 2008. There was none. source of external financing.

The study had a prospective, randomized, open-label, and end-point blind design. Eligible consenting patients with established coronary artery disease who presented for routine clinical review were randomized to receive 0.5 mg / day of colchicine or no colchicine without any other change in their medical treatment. All outcomes were evaluated by an experienced decision-making body blinded to treatment allocation.

Study size and eligibility: We planned to select a study population that included 250 patients, 28 randomized to the control group and 250 patients randomly assigned to treatment who were tolerant of colchicine for at least 4 weeks after the date of study. its randomization. Patients were eligible for inclusion in the study if they met each of the following criteria: 1) coronary artery disease proven by angiography; 2) from 35 to 85 years old; 3) clinically stable for at least 6 months, 4) with no major concurrent comorbidities or contraindications to colchicine therapy, 5) considered compliant with treatment and attending routine cardiology follow-up appointments, and 6) willing to receive a consent request and be randomly assigned to the study. Patients with a history of bypass surgery were only eligible if they had undergone bypass surgery more than 10 years prior, or had angiographic evidence of graft rejection, or had undergone stent implantation since bypass surgery. All patients signed the informed consent before randomization.

Randomization: The randomization sequence was computer generated, hidden from investigators at all times, and managed by a research assistant who was not involved in the evaluation or management of study patients. Once the consent form was received by the assistant, patient demographics were entered into the database and investigators and patients were informed in writing about the treatment group to which the patient had been assigned. Despite opting to use the lowest available dose of colchicine, it was anticipated that several patients would drop out soon after randomization due to gastrointestinal side effects. To ensure that the required number of patients in the treatment group were actually able to tolerate the treatment, the protocol allowed the research assistant to assign a newly selected patient to treatment if a patient discontinued colchicine treatment due to side effects during the first month. Patients who were intolerant to treatment remained in the study, underwent routine follow-up, and were included in the first intention-to-treat analysis.

Intervention: the referring cardiologist of each patient randomly selected for active treatment prescribed 0.5 mg of colchicine per day. The medicine was dispensed by their regular pharmacist and, upon request, patients were reimbursed for the cost of these prescriptions. The rest of the treatments were continued as usual.

Follow-up and definition of clinical outcomes: Patient compliance with treatment and outcome data were collected at routine follow-up visits and at the time of any unforeseen hospital admission. An acute coronary syndrome (ACS) was defined as (a) an acute myocardial infarction (AMI), manifested in the form of acute ischemic chest pain associated with an increase in serum troponin above the upper limit of normal, or a (b) Unstable angina (LA), manifested as a recent acceleration of the patient's angina not associated with an increase in serum troponin, but associated with angiographic evidence of a change in the patient's coronary anatomy. (Braunwald classification of unstable angina types IB and IIB.) ACS was characterized as stent-related if there was evidence of significant stenosis within the stent or acute stent thrombosis. Out-of-hospital cardiac arrest was defined as sudden death as stated on the patient's death certificate, or non-fatal out-of-hospital cardiac arrest, defined as recovery from a sudden collapse associated with documented asystole, ventricular tachycardia, or ventricular fibrillation. Non-cardioembolic ischemic stroke was defined as an ischemic stroke ascertained by CT or MRI that the treating neurologist judged was not due to atrial fibrillation or intracranial hemorrhage.

The primary efficacy outcome was mixed, ACS, fatal or non-fatal out-of-hospital cardiac arrest, or non-cardioembolic ischemic stroke. Secondary outcomes were (a) the individual components of the primary outcome and (b) the ACS components not related to stent disease.

Timing: The prespecified study duration was a minimum follow-up of two years in all patients. Consequently, the study was closed on May 31, 2012. During May, all living patients were contacted by phone to collect compliance and outcome data since the last follow-up date. Final outcome data were available in all patients and no patients were lost to follow-up.

Statistical power: assuming the control group had a combined event rate (ACS, out-of-hospital cardiac arrest, or non-cardioembolic ischemic stroke) of 8%, a 2-year accumulation interval, and a follow-up after the 2-year accumulation interval , the predicted sample size provided> 80% power to detect a hazard ratio of <0.50 based on a 2-sided significance level of 5%.

Data analysis: Summary statistics, including mean and standard deviation, were calculated for all baseline characteristics by treatment group. All time to episode results were calculated in days by subtracting the date of randomization from: (1) the date of the episode or death; or (2) the trial end date for those patients who did not experience the defined episode. As previously specified, the main efficacy analysis was based on the intention-to-treat principle. The intention-to-treat analysis included all randomized subjects and all episodes during the period. ranging from randomization to completion of the trial. The trial end date was set as May 31, 2012. A prespecified secondary analysis was also performed during treatment, based on patients who tolerated and were in compliance beyond the first month of randomization. All episodes during the period from randomization to non-adherence to the colchicine regimen were included in this analysis.

Time to first episode for all outcomes is presented using a Kaplan-Meier plot. The primary efficacy outcome was analyzed using a Cox proportional hazards model that included the treatment group coded as control or colchicine. Secondary outcomes were analyzed in a similar way. In addition, the primary analysis was stratified by sex, age, diagnosis of diabetes, previous myocardial infarction, unstable angina, coronary artery bypass surgery, coronary angioplasty and treatment with aspirin, clopidogrel or both, treatment with high-dose statins (defined as a atorvastatin equivalent statin doses of 40 mg or more), beta-blockers, calcium blockers, and ACE inhibitors.

Results: Between August 2008 and May 2010, 901 patients with stable coronary disease attending a routine outpatient cardiology review were evaluated for study eligibility. Of these, 297 (33%) did not meet the inclusion criteria, 72 (8%) refused to participate, and 532 (59%) enrolled in the study, 250 of whom were randomly assigned to the control group and, 282, to treatment. Of those randomized to treatment, 32 (11%) reported early intolerance, due to gastrointestinal side effects, and 7 patients subsequently reported deciding not to initiate treatment. The 532 randomized patients were followed up during the study period, which ranged from a minimum of 24 to a maximum of 44 months. The mean follow-up was 36 months.

Responses: There was a primary outcome in 55/532 patients, including 15/282 (5.3%) patients assigned to colchicine treatment and 40/250 (16%) patients assigned to the control group (hazard ratio 0.33 , 95% CI, 0.18-0.59, p <0.001, number needed to treat 11). A sensitivity analysis was performed for the primary outcome, adjusting the use of calcium channel blockers and treatment with beta-blockers. These results were consistent with the primary analysis.

The effect of colchicine on the primary outcome was evident from the beginning and the benefits of colchicine continued to accrue throughout the follow-up period. There was no evidence of differential treatment effects based on any of the clinical or therapeutic variables.

The reduction in the primary outcome was largely due to the reduction in the number of patients who had ACS, (13/282 (4.6%) vs 34/250 (13.4%), hazard ratio 0 , 33, 95% CI, 0.18-0.63, p <0.001). Out-of-hospital cardiac arrest and non-cardioembolic ischemic stroke were rare, but were also reduced in the treatment group.

Of the 47 patients who had ACS, the event was related to the stent in 8 (17%) (2 in each group showed signs of acute stent thrombosis and 2 in each group showed signs of significant stenosis inside the stent) . Further analysis confirmed that patients randomized to treatment were less likely to have ACS unrelated to stent disease (9/282 [3.2%] vs 30/250 [12%], hazard ratio 0.26, 95% CI; 0.12-0.55; p <0.001), either associated with AMI (4/282 [1.4%] vs 14/250 [5.6%], hazard ratio 0.25, 95% CI, 0.08-0.76, p = 0.014) or an LA (5/282 [1.8%] vs 16/250 [6.4%], ratio risk 0.27, 95% CI, 0.10-0.75, p = 0.011).

Of the 39 patients randomized to treatment who received no treatment beyond the first month due to early intolerance or non-compliance, 4 (10%) had ACS from acute stent thrombosis (n = 1) and IA (n = 3). Patients who met and tolerated treatment beyond the first month of randomization had significantly fewer episodes than control patients (11/243 [4.5%] vs 40/250 [16%], hazard ratio 0.29 , 95% CI, 0.15-0.56, p <0.001). The results of all on-treatment analyzes were consistent with those based on intention-to-treat analyzes.

Ten patients in the control group died compared to 4 patients in the colchicine group. Of the 10 control patients, 5 died of a suspected cardiac cause; 2 after out-of-hospital cardiac arrest, 2 due to cardiogenic shock after myocardial infarction, and 1 after bypass surgery. All 4 patients in the colchicine group died of non-cardiac causes.

This trial demonstrates that adding colchicine 0.5 mg / day to standard therapy in patients with stable coronary disease significantly reduces the risk of a cardiovascular event, including ACS, out-of-hospital cardiac arrest, and non-cardioembolic ischemic stroke. The benefits of colchicine were achieved in a context of widespread use of effective secondary prevention strategies, including high-dose statins, as evidenced by the low event rate in the control group. The effect of adding colchicine was apparent early on, continued to accumulate over time, and was largely driven by a reduction in ACS not related to stent disease.

Example 7: Dose adjustments of sustained-release colchicine formulations

To determine appropriate dose amounts, the sustained release formulation can be administered to patient populations of different body weights. Assuming that a 0.5 mg tablet gives a certain plasma level of colchicine in medium-weight patients and that this specific level must be achieved in each patient to be effective, a pharmacokinetic analysis of a 0.5 mg tablet can be performed. in different weight groups. Blood levels (Cmax and AUC) in overweight patients are expected to be lower, indicating that the dose needs to be adjusted towards higher doses.

Research objective: the main objective of this study is to compare the pharmacokinetics of a 0.5 mg colchicine tablet in healthy human volunteers of at least 2 different body weight groups. Specifically, blood levels of colchicine will be assessed during treatment. The proven hypothesis is that the administration of the same amount of colchicine results in different levels of colchicine as a function of body weight. Body weight and colchicine levels are inversely correlated.

General Study Design: This study has been designed as a randomized crossover study. n = at least 8 subjects are selected based on body weight. If 2 groups are made, then 50% will be low weight (eg less than 65 kg) and 50% high weight (eg more than 90 kg).

Study Duration: Study drug is given one time. The study consists of 24 h blood PK (high frequency data collection).

Research techniques and data analysis: Analytical chemistry techniques (HPLC) or immunological techniques (radioimmunoassay) can be used for the evaluation of colchicine. The collected data is analyzed using appropriate statistics and data management software.

Study population: the study population consists of healthy male volunteers. To be included in the study, the patient must be between 25 and 40 years old; not less than 50 kg and not more than 120 kg of body weight; be healthy; no major concurrent comorbidities or contraindications to colchicine treatment; be willing to consent and be randomized into the study. Patients who meet the following criteria will be excluded: ongoing treatment with other anti-inflammatory / immunosuppressive drugs; drug treatment with known drug interactions with colchicine; kidney / liver failure; known hypersensitivity to colchicine.

Treatment scheme: in the study, the drug is administered once in the morning.

Data Collection Scheme: For blood PK, blood will be collected over a 24 hour period at the start of the study at short intervals (sufficient time points to establish pharmacokinetic data, for example: -1, 0.5 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h, 15 h and 24 h (before next application). Additional time points can be 24 h and 72 h after drug withdrawal at the end of the study to examine the drug washout phase.

Example 8: Non-clinical pharmacokinetic study of sustained release (LM) versus immediate release (IL) of colchicine

A sufficiently high number of suitable laboratory animals are used in this experiment (eg, rodents such as mice or rats; at least 5 animals per group). The controller medicine is a colchicine LI tablet. The test drug is a colchicine LM tablet.

The control group of mice receives a first single dose of LI colchicine at a concentration within the therapeutic window (the range of colchicine plasma levels in which a therapeutic effect can be observed. It will be arbitrarily determined and set in the species of laboratory animals used as a maximum level sufficiently below the LD50 and a minimum level approximately 6 times lower than the maximum level). The test group receives a first single dose of LM colchicine in the same concentration. Blood is drawn from both groups at time points 0.25 h, 0.5 h, 0.75 h, 1 h, and thereafter every hour for 12 h and every 3 h until 24 h. At the same time, the faeces are removed from the cages of the test and control animals after 3, 6, 12 and 24 hours (the test and control animals should not be placed in the same cages).

Primary reading: plasma levels of colchicine. Secondary reading: determination of colchicine and its metabolites in feces to see if enterohepatic recirculation occurs to a lesser extent in test animals compared to control animals. Blood samples are processed and colchicine levels in blood plasma are measured by HPLC analysis or an equivalent quantitative method.

Results: The experiment is expected to show that the total absorption of colchicine (area under the curve) is similar in the test and control animals. However, in control animals, colchicine absorption peaks after approx. 1 h after administration and thereafter rapidly decreases. After 2-3 h, colchicine levels are below the therapeutic range. In addition, due to enterohepatic recirculation of unmetabolized colchicine, a reabsorption occurs that manifests itself in the characteristic secondary peak after 3-6 h.

However, in test animals (LM), the levels of colchicine will increase more slowly and will not reach the maximum levels of colchicine as observed in the control animals. Peak levels are observed after 3-8 hours and then slowly decrease. Therapeutic colchicine levels are maintained for at least 12 hours. Due to the more complete metabolization of colchicine in the liver, enterohepatic recirculation occurs to a lesser extent and a secondary peak cannot be observed. As a secondary reading, the feces of the test and control animals have been investigated to see if enterohepatic recirculation occurs to a lesser extent in the test animals compared to the control animals. It can be shown that the ratio of unchanged colchicine to metabolized colchicine is higher in control animals than in test animals. Therefore, LM colchicine results in a more complete metabolism of colchicine in the liver.

Example 9: Non-clinical safety study of LM vs. Colchicine LI

A sufficiently high number of suitable laboratory animals are used in this experiment (eg, rodents such as mice or rats; at least 5 animals per group). The controller medicine is a colchicine LI tablet. The test drug is a colchicine LM tablet.

The control group of mice receives a colchicine dose of LI / day at a concentration within the therapeutic window (the range of colchicine plasma levels in which a therapeutic effect can be observed. It will be arbitrarily determined and established in the species of laboratory animals used as a maximum level sufficiently below the LD50 and a minimum level approximately 6 times lower than the maximum level). The test group receives a colchicine dose of LM / day in the same concentration. Alternatively, test and control animals are given a total of two doses / day, one in the morning and one in the evening. The duration of the experiment is 2 weeks.

The primary reading is the incidence of gastrointestinal adverse events (eg, colic, diarrhea, etc.). This is evaluated in 3 ways. On a daily basis, the behavior of the tested animals is observed with a predetermined standardized method in which signs of disease are investigated. Second, feces are investigated daily for morphology and the presence of apoptotic epithelial cells. Third, individual animals are sacrificed at predetermined time points and the small and large intestines are investigated for histopathological signs of colchicine toxicity.

Results: During the course of the experiment, control animals can be expected to suffer more gastrointestinal adverse events than test animals. Therefore, LM colchicine has a better safety profile than LI colchicine.

Example 10: Clinical Safety Study of LM vs. Colchicine LI

If laboratory animals are unsuitable for investigation of colchicine-related adverse effects, an equivalent human experiment is carried out. It is carried out in healthy adult volunteers or, additionally, in patients who need colchicine. A sufficiently large number of human beings are used to achieve statistical significance. The test and control medication consists of an oral solid dosage form of colchicine LM or LI in a concentration of 0.25-1 mg. A dose high enough to achieve therapeutic levels of colchicine is administered. Alternatively to once daily administration, the tested drugs are administered twice daily as indicated in Example 3 above. Alternatively, to control for the placebo effect, a placebo group is included in both experimental settings. The duration of the experiment is between 2 weeks and 1 month.

Claims (9)

1. A sustained-release formulation of colchicine as an active ingredient, the formulation of which comprises: (a) granules comprising 0.1-0.6 mg of colchicine or a pharmaceutically acceptable salt thereof; (b) a binder, in which the binder is hydroxypropylmethylcellulose (HPMC) of 6 mPa · s in an amount of 1% to 30% (p.h.) of the formulation; (c) a retarding agent in an amount of 5% to 40% (ph) of the formulation, wherein the retarding agent is a spray-bonded mixture of equal parts by weight of HPMC with a viscosity grade of 4000 mP's and lactose monohydrate (Retalac®); and (d) at least one pharmaceutically acceptable excipient mixed with the granules, wherein the sustained release formulation is a tablet. 2. The formulation of claim 1, wherein: the pharmaceutically acceptable excipient is selected from the group consisting of a diluent, a glidant, and a lubricant, or a combination thereof; wherein the diluent is selected from the group consisting of sucrose, lactose, specifically lactose monohydrate, trehalose, maltose, mannitol and sorbitol, croscarmellose sodium, crospovidone, alginic acid, sodium alginate, methacrylic acid, divinylbenzene (DVB), cross-linked polyvinylpyrrolidone (cross-linked PVP ), microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch and combinations thereof, and in which the total amount of diluent in the formulation is between approximately 5.0% by weight and 90.0% % of the weight of the formulation; wherein the glidant is selected from the group consisting of colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, talc, and tribasic calcium phosphate; optionally wherein the total amount of glidant in the formulation is between about 0.5% by weight and about 5% by weight of the formulation; and wherein the lubricant is selected from the group consisting of glyceryl behenate, stearic acid, hydrogenated vegetable oils, stearyl alcohol, leucine, polyethylene glycol, magnesium stearate, glyceryl monostearate, polyethylene glycol, ethylene oxide polymers, sodium lauryl sulfate, lauryl sulfate of magnesium, sodium oleate, sodium stearyl fumarate, DL-leucine and colloidal silica, in which optionally the lubricant is included in an amount that is between approximately 0.5% by weight and approximately 5% by weight of the formulation. The formulation of claim 1 or claim 2, wherein the compressive strength of the tablet is between about 30N and about 130N. 4. The formulation of any of claims 1-3, for use in the prevention or treatment of cardiovascular disease, wherein optionally the cardiovascular disease is selected from the group consisting of acute pericarditis, recurrent pericarditis, post-pericardiotomy syndrome ( PPS) and cardiovascular events in patients with stable coronary disease. The formulation for use according to claim 4, wherein the formulation is used in conjunction with conventional treatment for the long-term prevention of an acute cardiovascular event in patients with established stable coronary disease, in which, optionally, said acute cardiovascular event is an acute coronary syndrome, an out-of-hospital cardiac arrest or a non-cardioembolic ischemic stroke, and optionally wherein the conventional treatment includes administration of a colchicine-compatible statin, wherein the colchicine-compatible statin is administered in a fixed or non-fixed combination with colchicine; optionally wherein the colchicine compatible statin is selected from the group consisting of atorvastatin, rosuvastatin, simvastatin and pravastatin, a derivative or a salt thereof. 6. The formulation of any of claims 1-3, for use in the prevention or treatment of an inflammatory disease, wherein optionally the inflammatory disease is selected from the group consisting of gout, familial Mediterranean fever, Behget's disease, macular degeneration associated with age and Alzheimer's disease. The formulation for use according to claim 6, wherein the total daily dose of colchicine administered to a subject is not more than about 0.75 mg. 8. A process of preparing a colchicine release tablet maintained comprising: (A) ^{forming a solution by dissolving colchicine in water, wherein the colchicine is supplied in such an} amount that the resulting tablet will comprise 0.25 to 0.75% (ph) of colchicine; (B) ^{Add a binder and a diluent to the solution from Step A, and form a wet granulate, in} which the binder is hydroxypropylmethylcellulose (HPMC) of 6 mPa ^ s and is added in such an amount that the resulting tablet comprises between 1 % and 30% (ph) of binder; (C) ^{drying the wet granulate from Step B;} (D) ^{Mixing the dry granulate from Step C with a retarding agent, a diluent, a slipper and a} lubricant, where the diluent is a spray-bonded mixture of equal parts by weight of HPMC with a viscosity grade of 4000 mPa ^ s and lactose monohydrate (Retalac®), and is added in such an amount that the resulting tablet comprises from 5 to 40% (ph) of retarding agent; and (E) ^{Compressing the final granulation from Step D into a tablet.} 9. The process of claim 8, wherein: in Step B, the diluent used is lactose monohydrate and pregelatinized starch; and in Step D the diluent used is lactose monohydrate, the slip used is talc and the lubricant used is stearic acid; o The specific ingredients and amounts used are: